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

• Sponsor: University of Alabama at Birmingham (Other)
• Overall Status: Completed
• CT.gov ID: NCT02096471
• Collaborator: (none)
• Enrollment: 19
• Locations: 11
• Arm: 1
• Duration (Months): 50
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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. 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

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

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

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: Aug 9, 2017
• Actual Study Completion Date: Aug 1, 2018

Arms and Interventions

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

1. Percent of Participants With a 20% or More Change in Target Tumor Volume [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..

Secondary Outcome Measures

1. Evaluable Participants Treated With PD-0325901 [baseline to 24 months]

   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

2. Toxicity of PD-0325901 [Baseline to 24 Months]

   Number and Percent of Participants with AEs and SAEs

3. The Objective Response Rate of up to 2 Non-Target Plexiform Neurofibromas to PD-0325901 [Baseline to 24 Months]

   radiographic response based on volumetric MRI measurements of up to 2 Non Target Plexiform Neurofibromas classified as complete, partial, stable or progressive

4. Area Under the Curve for the Parent Compound [Day 1; Course 1]

   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.

5. Quality of Life Using the Pain Subscale of the NRS-11 and PedsQL™ NF1 for Subjects Receiving PD-0325901 Using Age-based Assessments [Baseline to 12 Months]

   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.

6. Area Under the Curve for the Metabolite Compound [Day 1; Course 1]

   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.

7. Mean Half-Life for the PD-0325901 Concentrations [Day 1; Course 1]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
2	Children's National Medical Center	Washington	District of Columbia	United States	20010
3	University of Chicago	Chicago	Illinois	United States	60637
4	Indiana Unversity	Indianapolis	Indiana	United States	46202
5	National Cancer Institute (NCI)	Bethesda	Maryland	United States	20892
6	Children's Hospital Boston	Boston	Massachusetts	United States	02115
7	Washington University - St. Louis	Saint Louis	Missouri	United States	63110
8	New York University Medical Center	New York	New York	United States	10016
9	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
10	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19096
11	University of Utah	Salt Lake City	Utah	United States	84132

Sponsors and Collaborators

• University of Alabama at Birmingham

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 20, 2018

More Information

Publications

None provided.

• Responsible Party: Bruce Korf, MD, Principal Investigator, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT02096471
• Other Study ID Numbers: WI176190
• First Posted: Mar 26, 2014
• Last Update Posted: Jan 10, 2019
• Last Verified: Dec 1, 2018

• Keywords provided by Bruce Korf, MD, Principal Investigator, University of Alabama at Birmingham: Neurofibromatosis Type 1 (Neurofibromas); PD-0325901; Radiographic Response; Inoperable Plexiform Neurofibromas
• Additional relevant MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma

Study Results

Participant Flow

Pre-assignment Detail	The study required at least 1 partial or complete response within the first 9 patients in order to complete recruitment.

Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
Period Title: Overall Study
STARTED	19
COMPLETED	6
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
Overall Participants	19
Age (Count of Participants)
<=18 years	3 15.8%
Between 18 and 65 years	16 84.2%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24.9 (6.4)
Sex: Female, Male (Count of Participants)
Female	12 63.2%
Male	7 36.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 10.5%
Not Hispanic or Latino	16 84.2%
Unknown or Not Reported	1 5.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 10.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 26.3%
White	8 42.1%
More than one race	3 15.8%
Unknown or Not Reported	1 5.3%
Region of Enrollment (Count of Participants)
United States	19 100%
MRI at Baseline (Count of Participants)
1 Target Number of Plexiform Neurofibromas	17 89.5%
1 Target and non target Plexiform Neurofibromas	2 10.5%

Outcome Measures

1. Primary Outcome

Title	Percent of Participants With a 20% or More Change in Target Tumor Volume
Description	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..
Time Frame	baseline to 24 months

Outcome Measure Data

Analysis Population Description

All 19 participants enrolled equivalent to intention to treat population

Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
Measure Participants	19
Complete response	0 0%
Partial response	8 42.1%
Stable response	11 57.9%
Progressive Disease	0 0%

2. Secondary Outcome

Title	Evaluable Participants Treated With PD-0325901
Description	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
Time Frame	baseline to 24 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
Measure Participants	19
Evaluable	8 42.1%
Failed to Achieve Comp/Partial Response	11 57.9%

3. Secondary Outcome

Title	Toxicity of PD-0325901
Description	Number and Percent of Participants with AEs and SAEs
Time Frame	Baseline to 24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
Measure Participants	19
SAEs	2 10.5%
AEs	19 100%

4. Secondary Outcome

Title	The Objective Response Rate of up to 2 Non-Target Plexiform Neurofibromas to PD-0325901
Description	radiographic response based on volumetric MRI measurements of up to 2 Non Target Plexiform Neurofibromas classified as complete, partial, stable or progressive
Time Frame	Baseline to 24 Months

Outcome Measure Data

Analysis Population Description

All participants were evaluated and the two with non-Plexiform Neurofibromas were assessed.

Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
Measure Participants	19
Complete response	0 0%
Partial response	0 0%
Stable response	2 10.5%
Progressive Disease	0 0%

5. Secondary Outcome

Title	Area Under the Curve for the Parent Compound
Description	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.
Time Frame	Day 1; Course 1

Outcome Measure Data

Analysis Population Description

18 of the 19 participants had PK samples drawn.

Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
Measure Participants	18
Mean (Standard Deviation) [ng/mL*hr/(mg/m^2Parent)]	219.1 (41.4)

6. Secondary Outcome

Title	Quality of Life Using the Pain Subscale of the NRS-11 and PedsQL™ NF1 for Subjects Receiving PD-0325901 Using Age-based Assessments
Description	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.
Time Frame	Baseline to 12 Months

Outcome Measure Data

Analysis Population Description

NRS-11 are on a scale of 0-10 with 0 being no pain, higher scores are greater intensity. BPI pain interference scale yields a total score (each item 0-10 and total score=mean all items) higher scores are more pain interference.Remaining items are initially a 5-point Likert scale (0-4) and transformed to a 0-100 scale with higher scores better QOL.

Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
Measure Participants	19
Overall Tumor Pain Change (Baseline - 12 mo.)	1.38 (0.84)
Most Important Tumor Pain (Baseline - 12 mo.)	2.10 (0.80)
Brief Pain Inventory (Baseline - 12 mo.)	0.89 (0.66)
Total Functioning (Baseline - 12 mo.)	-3.77 (3.60)
Physical Functioning (Baseline - 12 mo.)	-3.55 (6.87)
Pain and Hurt (Baseline - 12 mo.)	-13.06 (8.29)
Movement and Balance (Baseline - 12 mo.)	-12.98 (6.35)
Daily Activities (Baseline - 12 mo.)	6.66 (5.05)
Emotional Functioning (Baseline - 12 mo.)	-2.34 (6.46)
Social Functioning (Baseline - 12 mo.)	-6.24 (6.79)
Cognitive Functioning (Baseline - 12 mo.)	-0.17 (6.37)
Communication Functioning (Baseline - 12 mo.)	0.68 (7.99)
Worry (Baseline - 12 mo.)	-10.97 (8.16)
Paresthesias (Baseline - 12 mo.)	-3.74 (6.58)
Skin Irritation (Baseline - 12 mo.)	-4.21 (5.51)
Sensation (Baseline - 12 mo.)	-6.27 (5.72)
Fatigue (Baseline - 12 mo.)	-0.71 (8.52)
Treatment Anxiety (Baseline - 12 mo.)	-1.07 (7.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single group change from baseline
	Type of Statistical Test	Superiority
	Comments	Single group study. Change in Pain from Baseline amongst those with a tumor response
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive analysis only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.38
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.84
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Pain from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.10
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.80
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Pain from Baseline amongst those with a Tumor Response
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.66
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life (QOL) from Baseline amongst those with a Tumor Response
Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.77
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.60
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study Change in Quality of Life from Baseline amongst those with a Tumor Response
Statistical Test of Hypothesis	p-Value	0.61
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.55
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.87
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study Change in Baseline amongst those with a Tumor Response
Statistical Test of Hypothesis	p-Value	0.12
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.06
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.29
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.98
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.35
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.66
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.05
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.72
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.34
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.46
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.24
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.74
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.37
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.99
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.97
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.16
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.74
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.58
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.45
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.21
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.51
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.27
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.72
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.71
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.52
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Agent PD-0325901
	Comments	Single Group Change from Baseline
	Type of Statistical Test	Superiority
	Comments	Single Group Study. Change in Quality of Life from Baseline amongst those with a Tumor Response.
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	t-test, 2 sided
	Comments	Descriptive Analysis Only
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.07
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.53
	Estimation Comments

7. Secondary Outcome

Title	Area Under the Curve for the Metabolite Compound
Description	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.
Time Frame	Day 1; Course 1

Outcome Measure Data

Analysis Population Description

18 of the 19 participants had PK samples collected and the metabolite compound AUC was computed and summarized.

Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
Measure Participants	18
Mean (Standard Deviation) [ng/mL*hr/(mg/m^2 Metabolite)]	91.1 (49.5)

8. Secondary Outcome

Title	Mean Half-Life for the PD-0325901 Concentrations
Description	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.
Time Frame	Day 1; Course 1

Outcome Measure Data

Analysis Population Description

18 of the 19 participants had PK samples collected and the metabolite compound AUC was computed and summarized.

Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
Measure Participants	18
Mean (Standard Deviation) [hours]	6.1 (3.5)

Adverse Events

Time Frame	Baseline to 24 Months
Arm/Group Title	Agent PD-0325901
Arm/Group Description	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. PD-0325901
All Cause Mortality
	Agent PD-0325901
	Affected / at Risk (%)	# Events
Total	0/19 (0%)
Serious Adverse Events
	Agent PD-0325901
	Affected / at Risk (%)	# Events
Total	2/19 (10.5%)
Gastrointestinal disorders
Abdominal Pain	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
Back Pain	1/19 (5.3%)	1
Pregnancy, puerperium and perinatal conditions
Pregnancy, puerperium and perinatal conditions, other	1/19 (5.3%)	1
Other (Not Including Serious) Adverse Events
	Agent PD-0325901
	Affected / at Risk (%)	# Events
Total	19/19 (100%)
Blood and lymphatic system disorders
Anemia	3/19 (15.8%)
Hemolysis	1/19 (5.3%)
Cardiac disorders
Sinus Tachycardia	1/19 (5.3%)
Ear and labyrinth disorders
Ear Pain	2/19 (10.5%)
Vertigo	1/19 (5.3%)
Eye disorders
Eye Disorder - Other, Pigment Changes	1/19 (5.3%)
Eye Disorder - Other, Subconjunctival Hemmorrhage of the Eye	1/19 (5.3%)
Eye Disorders - Other, Choroidal Space Macular	1/19 (5.3%)
Eye Disorders - Other, Nuclear Lens Opacification	1/19 (5.3%)
Eye Disorders - Other, Optic Nerve Drusen	1/19 (5.3%)
Eye Pain	1/19 (5.3%)
Gastrointestinal disorders
Abdominal Distension	1/19 (5.3%)
Abdominal Pain	3/19 (15.8%)
Bloating	1/19 (5.3%)
Constipation	4/19 (21.1%)
Diarrhea	6/19 (31.6%)
Dry Mouth	2/19 (10.5%)
Dyspepsia	1/19 (5.3%)
Gastritis	1/19 (5.3%)
Gastroesophageal Reflux Disease	1/19 (5.3%)
Gastrointestinal disorders - Other, Blood in Stool	1/19 (5.3%)
Gastrointestinal disorders - Other, Duodenitis	1/19 (5.3%)
Gastroparesis	1/19 (5.3%)
Mucositis oral	1/19 (5.3%)
Nausea	12/19 (63.2%)
Oral Pain	1/19 (5.3%)
Rectal hemmorrhage	1/19 (5.3%)
Vomitting	7/19 (36.8%)
General disorders
Chills	1/19 (5.3%)
Edema Face	1/19 (5.3%)
Edema Limbs	2/19 (10.5%)
Fatigue	11/19 (57.9%)
Flu-like Symptoms	3/19 (15.8%)
Localized Edema	1/19 (5.3%)
Pain	2/19 (10.5%)
Infections and infestations
Conjunctivitis Infective	1/19 (5.3%)
Mucosal Infection	1/19 (5.3%)
Paronychia	2/19 (10.5%)
Sinusitis	1/19 (5.3%)
Tooth Infection	1/19 (5.3%)
Upper Respiratory Infection	3/19 (15.8%)
Investigations
Alkaline Phosphatase Increased	1/19 (5.3%)
Aspartate Aminotransferase Increased	2/19 (10.5%)
Blood Bilirubin Increased	1/19 (5.3%)
CPK Increased	6/19 (31.6%)
Creatinine Increased	1/19 (5.3%)
Hemoglobin Increased	1/19 (5.3%)
Hiatal Hernia	1/19 (5.3%)
Indigestion	1/19 (5.3%)
Lymphocyte Count Decreased	2/19 (10.5%)
Lymphocyte Count Increased	1/19 (5.3%)
Neutrophil Count Decreased	1/19 (5.3%)
Platelet Count Decreased	2/19 (10.5%)
Weight Gain	3/19 (15.8%)
White Blood Cell Count Decreased	1/19 (5.3%)
Metabolism and nutrition disorders
Anorexia	1/19 (5.3%)
Dehydration	1/19 (5.3%)
Hypercalcemia	1/19 (5.3%)
Hyperglycemia	4/19 (21.1%)
Hypermagnesemia	2/19 (10.5%)
Hypernatermia	1/19 (5.3%)
Hypoalbuminemia	5/19 (26.3%)
Hypocalcemia	4/19 (21.1%)
Hyerkalemia	1/19 (5.3%)
Hypoglycemia	1/19 (5.3%)
Hypokalemia	4/19 (21.1%)
Hypomagnesemia	4/19 (21.1%)
Hyponatremia	2/19 (10.5%)
Hypophosphatemia	2/19 (10.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/19 (5.3%)
Back Pain	3/19 (15.8%)
Fibrosis Deep Connective Tissue	1/19 (5.3%)
Flank Pain	1/19 (5.3%)
Musculoskeletal and connective tissue disorders - Other, Hip Pain	1/19 (5.3%)
Myalgia	1/19 (5.3%)
Pain in Extremity	4/19 (21.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (inc cysts and polyps) - Other, Cyst	1/19 (5.3%)
Nervous system disorders
Dizziness	6/19 (31.6%)
Headache	8/19 (42.1%)
Movements involuntary	1/19 (5.3%)
Paresthesia	2/19 (10.5%)
Seizure	2/19 (10.5%)
Spasticity	1/19 (5.3%)
Syncope	1/19 (5.3%)
Psychiatric disorders
Agitation	1/19 (5.3%)
Anxiety	1/19 (5.3%)
Confusion	1/19 (5.3%)
Insomnia	1/19 (5.3%)
Renal and urinary disorders
Cystitis noninfective	1/19 (5.3%)
Urinary incontinence	1/19 (5.3%)
Reproductive system and breast disorders
Irregular menstruation	1/19 (5.3%)
Reproductive system and breast disorders - other, breakthrough bleeding	1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Cough	2/19 (10.5%)
Epistaxis	2/19 (10.5%)
Nasal congestion	2/19 (10.5%)
Pneumonitis	1/19 (5.3%)
Skin and subcutaneous tissue disorders
Alpecia	2/19 (10.5%)
Dry Skin	1/19 (5.3%)
Hirsutism	1/19 (5.3%)
Hyperhidrosis	1/19 (5.3%)
Night sweats	1/19 (5.3%)
Pruritus	3/19 (15.8%)
Rash maculopapular	2/19 (10.5%)
Rash acneiform	18/19 (94.7%)
Rash pustular	1/19 (5.3%)
Skin and subcutaneous tissue disorders - Other, Bleeding and oozing from ear	1/19 (5.3%)
Skin and subcutaneous tissue disorders - Other, Erythema hallux	1/19 (5.3%)
Skin and subcutaneous tissue disorders - Other, Erythema	1/19 (5.3%)
Skin and subcutaneous tissue disorders - Other, Hemangiomas	1/19 (5.3%)
Skin and subcutaneous tissue disorders - Other, Oily Skin	1/19 (5.3%)
Skin and subcutaneous tissue disorders - Other, Pustular Dermatosis	1/19 (5.3%)
Vascular disorders
Hypertension	2/19 (10.5%)
Vascular disorder - Other, Hot Flashes	1/19 (5.3%)

Limitations/Caveats

None to report.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.