Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Blood and Lymph Conditions

Immune System Diseases

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Lymphoma

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Lymphosarcoma

Neurofibromatosis

Neurofibromatosis Type 1

Antineoplastic Agents

All Drugs and Chemicals

Cetuximab

Mitogens

Antineoplastic Agents, Immunological

Monotherapy dose escalation of PF-07284892 in participants with ALK- or ROS1-positive non-small cell lung cancer (NSCLC), B-type Raf proto-oncogene V600E mutation colorectal cancer (CRC), or RAS- mutant, NF1-mutant or BRAF class 3-mutant solid tumors

Combination dose escalation of PF-07284892 in combination with lorlatinib in participants with ALK- or ROS1-positive NSCLC

PF-07284892 + lorlatinib in participants with ALK+ NSCLC with prior lorlatinib

PF-07284892 + lorlatinib in participants with ALK+ NSCLC with no prior lorlatinib

PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with prior BRAF inhibitor (BRAFi) plus epidermal growth factor receptor inhibitor (EGFRi)

PF-07284892 + encorafenib + cetuximab in participants with BRAF V600E mutant CRC with no prior BRAFi plus EGFRi

PF-07284892 + binimetinib in participants with RAS- mutant, NF1-mutant or BRAF class 3 mutant solid tumors who have received prior standard of care (SOC)

Combination dose escalation of PF-07284892 in combination with encorafenib and cetuximab in participants with BRAF V600E mutant CRC

Combination dose escalation of PF-07284892 in combination with binimetinib in participants with Ras-mutant, NF-1 mutant or BRAF class 3 -mutant solid tumors

PF-07284892

lorlatinib

binimetinib

cetuximab

encorafenib

Pfizer CT.gov Call Center

The purpose of this first-in-patient, open label study is to determine the maximum tolerated dose and/or recommended dose for further study of PF-07284892 as a single agent and in combination with lorlatinib, encorafenib and cetuximab, or binimetinib and evaluate the pharmacokinetics, safety, and preliminary clinical activity of single agent and each combination therapy.

PF-07284892 in Participants With Advanced Solid Tumors

A PHASE 1, OPEN-LABEL, MULTI-CENTER, DOSE ESCALATION AND DOSE EXPANSION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PRELIMINARY EVIDENCE OF ANTI-TUMOR ACTIVITY OF PF-07284892 (ARRY-558) AS A SINGLE AGENT AND IN COMBINATION THERAPY IN PARTICIPANTS WITH ADVANCED SOLID TUMORS

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

DLTs will be evaluated during the first cycle (21 days) as both a single agent or in combination with lorlatinib, encorafenib + cetuximab, or binimetinib. The number of DLTs will be used to determine the maximum tolerated dose (MTD)/recommended dose for further study

AEs as characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy

Laboratory abnormalities as characterized by type, frequency, severity, and timing

Incidence of dose interruptions, dose modifications, and discontinuations due to AEs

Response will be evaluated via radiographical tumor assessments by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)

single dose (Cmax) and multiple dose (assuming steady state is achieved; Css,max) pharmacokinetic (PK) parameters

Single dose (Tmax) and multiple dose (assuming steady state is achieved; Tss,max) pharmacokinetic parameters

Single dose and multiple dose (assuming steady state is achieved) PK parameter

Multiple dose (assuming steady state is achieved) PK parameter

Response will be evaluated via radiographical tumor assessments by RECIST v1.1

Time from the first documentation of objective response to the first documentation of objective progressive disease, relapse or to death due to any cause

Pfizer

Symptoms and General Pathology

Skin and Connective Tissue Diseases

Neurofibroma, Plexiform

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Syndrome

Neoplastic Syndromes, Hereditary

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Peripheral Nervous System Diseases

Neuromuscular Diseases

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Mirdametinib (PD-0325901) capsule or dispersible tablet 2 mg/m\^2 (maximum dose of 4 mg) by mouth twice daily

Mirdametinib (PD-0325901) capsule or dispersible tablet

Mirdametinib (PD-0325901) oral capsule or dispersible tablet

Christopher L Moertel, MD

This study evaluates mirdametinib (PD-0325901) in the treatment of symptomatic inoperable neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PNs). All participants will receive mirdametinib (PD-0325901). Eligible participants may continue in a long-term follow-up phase.

Neurofibromas are benign peripheral nerve sheath tumors, which are classified as plexiform neurofibromas (PNs) if they extend longitudinally along a nerve and involve multiple fascicles. PNs are a major cause of morbidity and disfigurement in individuals with NF1, and as the tumor growth progresses, can cause a multitude of clinical deficits including pain and impaired physical function. PNs have the potential to undergo malignant transformation to Malignant Peripheral Nerve Sheet Tumors (MPNST).

Mirdametinib (PD-0325901) is an orally delivered, highly selective small-molecule inhibitor of the dual specificity kinases, MEK1 and MEK2 (MAPK/ERK Kinase) which prevents the phosphorylation and subsequent activation of mitogen-activated protein kinase (MAPK).

Previous studies of mirdametinib (PD-0325901) demonstrated PN shrinkage and sustained inhibition of pERK. Reduced tumor volume indicated that cell proliferation or cell death may be altered in PNs with administration of mirdametinib (PD-0325901).

All participants will receive mirdametinib (PD-0325901) at a dose of 2 mg/m\^2 twice daily (maximum dose of 4 mg twice daily), calculated based on body surface area. Dose will be administered in a 3-week on, 1-week off schedule.

MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas

A Phase 2b Trial of the MEK 1/2 Inhibitor (MEKi) PD-0325901 in Adult and Pediatric Patients With Neurofibromatosis Type 1 (NF1)-Associated Inoperable Plexiform Neurofibromas (PNs) That Are Causing Significant Morbidity

SpringWorks Therapeutics is committed to data transparency and sharing data to further research while maintaining the privacy and confidentiality of research participants. Pertinent patient-level data from completed registrational clinical trials will be made available by SpringWorks to qualified researchers upon approval of reasonable requests following de-identification/anonymization pursuant to applicable law.

PROMIS measures capability of physical functioning, with questions related to daily activities. Participants ≥ 18 years of age complete a self-report of physical function. Participants 8-17 years of age complete a self-report of physical function in the upper extremity or lower extremity (mobility), depending on location of the PN. Parents/guardians of children ages 2-17 complete a parent proxy report corresponding to the pediatric version. The recall period is 7 days.

If motor dysfunction or weakness is evident, strength of the affected muscle groups will be measured by dynamometer and assessed by a muscle grading scale.

If motor dysfunction or weakness is evident, range of motion of the affected areas and/or joints will be measured by a goniometer.

If airway or lower extremity motor dysfunction is evident, endurance will be measured by completion of a 6-minute walking test.

Response will be determined by a blinded centralized review of volumetric MRI.

Evidence of progression or tumor growth will be determined by a blinded centralized review of volumetric MRI.

For participants with a PN that is visible and amenable to photography, changes in visible tumor aspects will be evaluated by a centralized reviewer.

Measured in tumor biopsies in participants ≥ 18 years of age.

The P-OMAQ uses a 5-point numerical rate scale to measure acceptability of use of the tablet formulation with questions related to taste, smell and administration of study medication. Participants ≥ 8 years of age complete a 12-item self-report; adult parents/caregivers responsible for oversight of study drug administration for participants ages 6 months to 17 years complete a 19-item caregiver report . The recall period is 7 days.

Adverse events will be assessed according to toxicities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

The PedsQL consists of a 23-item core measure of global QOL that can be completed in approximately 5 minutes. There are four subscales: physical functioning, emotional functioning, social functioning and school/work functioning. Participants ≥ 5 years of age complete an age-appropriate self-report; and parents/guardians of children ages 2-17 complete a parent proxy report of the age-specific QOL. The recall period is 7 days.

The NRS-11 is a self-reported 11-point numerical scale that assesses pain severity. Participants ≥ 8 years of age are asked to select a number from 0 (no pain) to 10 (worst pain you can imagine) that best describes their worst pain. The recall period is 24 hours.

The PII assesses relevant aspects of one's life, including pain interference with activities, spending time with family/friends, mood, sleep and attention. Participants ≥ 6 years of age complete a self-report, and parents/guardians of children age 6-17 complete a parent proxy report. The recall period is 24 hours.

SpringWorks Therapeutics, Inc.

Bone Density Conservation Agents

Micronutrients

Vitamins

Vitamin D

Cholecalciferol

Trace Elements

Hormones

Calcium

Calcium, Dietary

Vitamin D3

Calciferol

cholecalciferol in Ddrops form at either 600 International units per day versus 4,000 IU per day

Cholecalciferol at 4,000 IU per day in the form of liquid Ddrops

DDrops(trademark) prepared two sets of bottles, one set has 300IU per metered dose and the other set has 2,000IU per metered dose. Participants are randomized to either 600 IU or 4,000 IU, and they take two measured drops orally, once a day. There is a dropper that automatically drops out a measured amount when the bottle is turned upside down.

David H. Viskochil, MD, PhD

This clinical trial is conducted by one of 4 locations; University of British Columbia (Vancouver, CA), University of Utah (Salt Lake City, UT, USA), University of Cincinnati (Cincinnati, OH, USA), and University of Hamburg (Hamburg, Germany).

Adults with NF1 have a higher risk of osteopenia and osteoporosis, a condition of low bone density that can lead to fragile bones and bone breakage.

People with NF1 also have lower vitamin D levels than unaffected individuals. Vitamin D is important for normal bone health, but studies to improve bone health by vitamin D supplementation in people with NF1 have not been tried.

The purpose of this study is to treat adults with NF1 who have insufficient serum vitamin D levels with 2 different doses of vitamin D supplementation to determine if vitamin D supplementation ameliorates the usual loss of bone mineral density over 2 years.

Individuals with NF1 and vitamin D insufficiency will be supplemented with 2 different doses of cholecalciferol (vitamin D) to see if their loss of bone mineral density is lessened over time. It is important to study vitamins as carefully as one would study medications, even though vitamins are generally safer than medications. For this reason, a carefully controlled trial of two doses of vitamin D will be performed over a 2-year period. It will include controlled doses and safety checks for participants' health to be sure that the vitamin D supplementation is safe for people with NF1.

Two different doses of cholecalciferol, either 600 IU or 4,000 IU (IU means "International Units" a standard measure of the strength of the dose), will be used for supplementation. The trial is "double blind". This means that neither participant nor investigator team know which dose an individual participant might be randomized to receive until after the trial ends. In an emergency, however, the investigator can find out.

Participants will be randomized to one or the other dose, and each participant will be provided a bottle of liquid called "D-drops" with a dropper that automatically drops out a measured amount when the bottle is turned upside down.

Both doses of vitamin D, 600 IU and 4,000 IU, have been approved in the general population; however, it is possible that the bodies of people with NF1 handle vitamin D differently. Therefore, safety measures are assessed during this trial. Any new medical issues or concerns throughout the 2-year period will need to be recorded and assessed with the study team.

The primary measure of this study is bone mineral density obtained by bone densitometry (DXA) using low-dose xrays. Bone mineral density will be tested at the beginning and the end of the trial focusing on density of bones in the hip and spine. Secondary measures of this trial include questionnaires that measure quality of life and history of bone fractures.

When someone is insufficient in serum vitamin D and supplementation is recommended, it is also supplemented with calcium. Therefore, participants will be given a calcium supplement of 400 mg elemental calcium per day. A diary to keep daily track of vitamin D and calcium supplementation and documentation of fractures, should they occur, is provided.

Vitamin D Supplementation for Adults With Neurofibromatosis Type 1 (NF1)

A Phase II Trial on the Effect of Low-Dose Versus High-Dose Vitamin D Supplementation on Bone Mass in Adults With Neurofibromatosis Type 1 (NF1)

Publication of all study data will be written

Serum samples will be analyzed for intact parathyroid hormone with calcium.

Serum samples will be analyzed for 25(OH) vitamin D

The primary outcome measure is a change in bone mineral density, which will be determined by bone densitometry at the beginning and at the end of the 2-year trial.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
PF-07284892 in Participants With Advanced Solid Tumors	NCT04800822	Solid Tumor	PF-07284892 lorlatinib binimetinib cetuximab encorafenib	18 Years -	Pfizer
MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas	NCT03962543	Plexiform Neuro... Neurofibromatos...	Mirdametinib (P...	2 Years -	SpringWorks Therapeutics, Inc.
Vitamin D Supplementation for Adults With Neurofibromatosis Type 1 (NF1)	NCT01968590	Neurofibromatos...	Cholecalciferol	25 Years - 40 Years	University of Utah
PF-07284892 in Participants With Advanced Solid Tumors	NCT04800822	Solid Tumor	PF-07284892 lorlatinib binimetinib cetuximab encorafenib	18 Years -	Pfizer
MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas	NCT03962543	Plexiform Neuro... Neurofibromatos...	Mirdametinib (P...	2 Years -	SpringWorks Therapeutics, Inc.

Spots Global Cancer Trial Database for neurofibromatosis type 1 (nf1)