ARQ 092 (Miransertib) in Proteus Syndrome
ARQ 092 (Miransertib) in Proteus Syndrome
Background:

 Proteus syndrome is a rare overgrowth disorder. Most people begin to have symptoms between 6
 months and 2 years of age. There are very few living adults with this disease. There is also
 no known treatment for it. Researchers want to see if a new drug can slow down or stop
 overgrowth in people with Proteus syndrome.

 Objective:

 The learn if miransertib is a safe and effective treatment for Proteus syndrome.

 Eligibility:

 People ages 3 and older with Proteus syndrome

 Design:

 Participants will be screened with a medical checkup. They will answer questions about their
 medical history and current health. They will have a physical exam with vital signs. They
 will have an electrocardiogram to measure their heartbeat. They will give blood and urine
 samples. They will repeat the screening tests during the study.

 Participants will take a miransertib pill once a day. They will bring their empty pill
 bottles with them to the NIH when they visit. If they can t swallow a pill, researchers will
 try to find other ways for them to take the drug.

 Participants will have X-rays, ultrasounds, and imaging scans. Photos may be taken of their
 feet and other parts of the body that have or develop signs of Proteus syndrome.

 Participants will have lung function tests to measure how much and how fast air moves out of
 their lungs.

 Participants will complete surveys about their levels of pain, physical functioning, and
 quality of life.

 Participants may have additional tests performed to assess their individual disease. They may
 have consultations with other specialists.

 Participation lasts about 4 years. Participants will have 20 30 visits at the NIH.

 ...
Proteus syndrome is a rare mosaic overgrowth disorder caused by a somatic gain of function
 variant, c. 49G>A, p.(Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase. The disorder
 is progressive, with high morbidity and mortality - there are very few living adults with
 this disease. Tissues and cell lines from patients with Proteus syndrome harbor admixtures of
 mutant alleles that ranged from <1% - 50%. This variant causes constitutive activation of
 AKT1, through Ser473 and Thr308 phosphorylation. This activation stimulates the AKT/PI3K
 pathway, mediating processes including increased cell proliferation and decreased apoptosis.
 The progressive nature of the disorder and the mechanism of disease (gain of function) make
 AKT1 an excellent target for therapeutics, specifically repression. The AKT/PI3K pathway is
 mutated in numerous cancers as well. Because it is commonly mutated in cancer, pharmaceutical
 companies are interested in targeting this molecule with inhibitors.

 ArQule Inc., a wholly owned subsidiary of Merck & Co., has developed a small molecule, ARQ
 092 [miransertib], that inhibits AKT, with an IC50 for AKT1, AKT2, and AKT3 that is orders of
 magnitude lower than other kinases. This agent has undergone significant development with
 animal toxicity studies and is currently in phase I trials in adult participants with
 different types of cancer. In addition, we have performed in vitrotesting with miransertib in
 cells from patients with Proteus syndrome and demonstrated reduction in AKT1 phosphorylation
 at doses in the range of achievable blood levels in humans with low toxicity. We have
 completed a phase 0/I study of miransertib in adults and older children with Proteus syndrome
 (NIH protocol 16-HG-0014). In this study, we demonstrated that 5 mg/m m^2/day was a
 well-tolerated dose which resulted in tissue drug levels consistent with our pre-clinical
 data-based pharmacodynamic target. As well, one of the participants from the phase I study
 felt so strongly about the benefits of the drug, both from a pain relief standpoint plus
 evidence of improvement in one of his skin lesions, that he and his family have requested
 continuation of the drug in that trial, as was offered to participants who felt that they had
 received significant benefit. This initial Cohort of participants was dosed at levels well
 below those tested previously in the oncology setting. In summary, with our phase 0/1trial,
 we gained invaluable experience with a number of therapeutic endpoints and showed some
 evidence of efficacy in two of six participants.

 We now propose a phase II non-randomized observation study assessing the efficacy of
 miransertib through assessment of the hallmark skin lesion of Proteus syndrome, the
 cerebriform connective tissue nevus (CCTN). The primary objective of this study is to
 determine the response rate of miransertib as measured by a change in CCTN lesion size
 relative to total plantar area from baseline, using blinded independent central review of
 lesional photography in at least 10 patients with Proteus syndrome (Cohort 1). Cohorts 2 and
 3 will enroll up to 30 additional patients whose non-plantar CCTN Proteus syndrome-
 associated lesions will be evaluated to address the secondary and exploratory study
 objectives. All participants will be treated with miransertib in continuous, 28-day cycles.
 Participants in Cohorts 1 and 2willreceivemiransertib at the starting dose of 15 mg/ m^2QD
 for the first three cycles, and then the dose will be increased to 25mg/m^2QD, provided no
 clinically significant drug-related toxicity is observed. Participants in Cohort 3 will
 receive miransertib at the dose they were on at the time of enrollment if continuing use of
 miransertib or at the starting dose for Cohorts 1 and 2 if resuming use of miransertib, not
 to exceed 25 mg/m m^2QD. Safety and toxicity data will be gathered on all participants.
 Participants will stay on treatment for up to 52 cycles. The final clinical safety follow-up
 will be performed 30 days after the last dose.
-  INCLUSION CRITERIA:

 All participants in all Cohorts must meet the criteria below:

 -  Signed informed consent, and when applicable, signed assent

 -  Have a molecular diagnosis of Proteus syndrome with documented somatic AKT1 mutation
 from a CLIA-certified laboratory.

 -  Have progressive and measurable disease (e.g., a measurable manifestation of Proteus
 syndrome with evidence or report of worsening of manifestation(s)/ in the last 12
 months)

 -  Adequate organ function as indicated by the following laboratory values:

 Hematological:

 -  Hemoglobin (Hgb) depending on age:

 -  2-5 years male and female: greater than or equal to 10.0 g/Dl

 -  6-9 years male and female: greater than or equal to 11.5 g/dL

 -  10-17 years female: greater than or equal to 11.0 g/dL

 -  10-17 years male: greater than or equal to 11.5 g/dL

 -  >17 years male and female: greater than or equal to 10.0 g/dL

 -  Glycated hemoglobin (HbA1c): less than or equal to 8% (less than or equal to 64
 mmol/mol)

 -  Absolute neutrophil count (ANC): greater than or equal to 1.5 x 10^9/L

 -  Platelet count greater than or equal to 150 x 10^9/L

 Hepatic:

 -  Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN)/L

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal
 to x ULN

 Renal:

 -Serum creatinine depending on age:

 -  2-5 years male and female: less than or equal to 0.50 mg/dL

 -  6-10 years male and female: less than or equal to 0.59 mg/dL

 -  11-15 years male and female: less than or equal to 1.2 mg/dL

 -  >15 years male and female: less than or equal to 1.5 mg/dL

 Metabolic (lipids):

 -  Cholesterol: less than or equal to 400 mg/dL (less than or equal to 10.34 mmol/L)

 -  Triglyceride: less than or equal to 500 mg/dL (less than or equal to 5.7 mmol/L)

 -  If a female is of child-bearing potential, documentation of a negative pregnancy
 test is required prior to enrollment. Sexually active participants (male and
 female) must agree to use double-barrier contraceptive measures, oral
 contraception, or avoidance of intercourse while on study and for up to 90 days
 after ending treatment

 -  Ability to complete the questionnaires by the participant and/or his/her
 caregiver

 The following specific criteria will be used to assign participants to Cohorts:

 Cohort 1 (Proteus syndrome with plantar CCTN) specific criteria:

 -  Have at least one plantar CCTN that can accurately be measured by standardized
 photography. The CCTN is defined as a nevus with at least two gyri and three sulci
 affecting 10% - 70% of the total surface area of the foot.

 -  Male or female participants age greater than or equal to 3 and less than or equal to
 16 years old and BSA of greater than or equal to 0.33 m^2

 Cohort 2 (Proteus syndrome without plantar CCTN) specific criteria:

 -  Does not meet the eligibility criteria for Cohorts 1 or 3

 -  Male or female participants age greater than or equal to 3 years old and BSA of
 greater than or equal to 0.33 m^2

 Cohort 3 (Proteus syndrome previously treated with miransertib) specific criteria:

 -  Participants previously treated with miransertib or currently receiving miransertib
 under Compassionate Use/Expanded Access or an existing trial (i.e., 16-HG-0014)

 -  Male or female participants greater than or equal to 3 years old and BSA of greater
 than or equal to 0.33 m^2

 Note: All participants must meet Cohort-related age criteria by/on the date of the first
 dose, Cycle 1 Day 1

 EXCLUSION CRITERIA:

 An individual who meets any of the following criteria will be excluded from participation
 in this study:

 -  History of Type 1 or Type 2 uncontrolled diabetes mellitus requiring regular
 medication (other than metformin or other oral hypoglycemic agents) or fasting glucose
 greater than or equal to 160 mg/dL ( if >12 years old) and greater than or equal to
 180 mg/dL (if less than or equal to 12 years old) at the baseline/screening visit

 -  History of significant cardiac disorders:

 -  Myocardial infarction (MI) or congestive heart failure defined as Class II-IV per
 the New York Heart Association (NYHA) classification within six months of the
 first dose of miransertib (MI occurring >6 months of the first dose of
 miransertib will be permitted)

 -  Grade 2 (per National Cancer Institute [NCI] Common Terminology Criteria for
 Adverse Events [CTCAE] current version) or worse conduction defect (e.g., right
 or left bundle branch block).

 -  Major surgery, radiotherapy, or immunotherapy within four weeks of the first dose of
 miransertib

 -  Any experimental systemic therapy for the purpose of treating Proteus syndrome (e.g.,
 sirolimus, everolimus, high dose steroids, alpelisib) within two weeks of the first
 dose of miransertib, except for participants who were previously or are currently
 treated with miransertib under a Compassionate Use/Expanded Access program or existing
 protocol

 --Participants who were previously treated with or currently are receiving miransertib
 will be enrolled and treated according to the Schedule of Assessments/Study Visits
 defined in this protocol

 -  Intolerance of, or severe toxicity attributed to, AKT inhibitors (e.g., miransertib,
 uprosertib, afuresertib, ipatasertib)

 -  Concurrent severe uncontrolled illness not related to Proteus syndrome

 -  Ongoing or active infection

 -  Known human immunodeficiency virus (HIV) infection malabsorption syndrome

 -  Psychiatric illness/substance abuse/social situation that would limit compliance
 with study requirements

 -  Pregnant or breastfeeding (contraception requirements can be found above and in the
 informed consent form)

 -  Inability to comply with study evaluations or to follow drug administration guidelines

 -  Concomitant use of a prohibited medication

 -  Regular tobacco use and/or use of cannabidiol/tetrahydrocannabidiol (CBD/THC), and/or
 vaping products