There are 3 clinical trials

Clinical Trials

1 A Phase I, Multi-center, Non-randomized, Open-label, Dose Escalation Design Study to Characterize Safety, Tolerability, Pharmacokinetics and Maximum Tolerated Dose of BAY 1125976 in Subjects With Advanced Solid Tumors

This is the first study where BAY1125976 is given to humans. Patients (all comers) will receive the study drug treatment in a dose-escalation scheme (no placebo group) to determine the safety, tolerability and maximum tolerated dose (MTD) of BAY1125976. The relative bioavailability of liquid service formulation and tablets will be determined. After the MTD is defined breast cancer patients with and without AKT1 mutation will be treated. The study will also assess the pharmacokinetics, biomarker status, pharmacodynamic parameters and tumor response of BAY1125976. BAY1125976 will be given daily as single oral application. Treatment will be stopped if the tumor continues to grow, if side effects, which the patient cannot tolerate, occur or if the patient decides to exit treatment.

NCT01915576 Neoplasms Drug: BAY1125976 Drug: BAY1125976 Drug: BAY1125976

In addition, the investigator must judge the experimental treatment as clinically and ethically acceptable - For expansion cohort only: Subjects with histologically or cytologically proven metastatic breast cancer (with and without AKT1 E17K (G49A) mutation) or subjects with known AKT1 E17K (G49A) mutation in any other advanced solid tumor with at least one line of chemotherapy in the metastatic setting and not amenable to surgery with curative intent - Subjects must have measurable disease (Response evaluation criteria in solid tumors (RECIST 1.1) - Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 2 - Bone marrow, liver and renal functions as assessed by adequate laboratory methods to be conducted within 7 days prior to starting study treatment - Subjects must provide tumor biopsies before treatment - Recovery to CTCAE (Common Terminology Criteria for Adverse Events Version 4.03) Grade 0 or Grade 1 or recovery to baseline preceding the prior treatment of any previous drug / procedure-related toxicity (except alopecia, anemia, and hypothyroidism) Exclusion Criteria: - History of cardiac disease including congestive heart failure > New York Heart Association (NYHA) Class II - Subjects with type 1 or type 2 diabetes mellitus - Subjects with fasting glucose >125 mg/dL in 2 independent measurements or glycated hemoglobin (HbA1c) ≥ 7% - Moderate and severe hepatic impairment, i.e. --- E17K ---

In addition, the investigator must judge the experimental treatment as clinically and ethically acceptable - For expansion cohort only: Subjects with histologically or cytologically proven metastatic breast cancer (with and without AKT1 E17K (G49A) mutation) or subjects with known AKT1 E17K (G49A) mutation in any other advanced solid tumor with at least one line of chemotherapy in the metastatic setting and not amenable to surgery with curative intent - Subjects must have measurable disease (Response evaluation criteria in solid tumors (RECIST 1.1) - Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 2 - Bone marrow, liver and renal functions as assessed by adequate laboratory methods to be conducted within 7 days prior to starting study treatment - Subjects must provide tumor biopsies before treatment - Recovery to CTCAE (Common Terminology Criteria for Adverse Events Version 4.03) Grade 0 or Grade 1 or recovery to baseline preceding the prior treatment of any previous drug / procedure-related toxicity (except alopecia, anemia, and hypothyroidism) Exclusion Criteria: - History of cardiac disease including congestive heart failure > New York Heart Association (NYHA) Class II - Subjects with type 1 or type 2 diabetes mellitus - Subjects with fasting glucose >125 mg/dL in 2 independent measurements or glycated hemoglobin (HbA1c) ≥ 7% - Moderate and severe hepatic impairment, i.e. --- E17K --- --- G49A --- --- E17K ---

2 A Pilot Study of AZD5363 for Patients With Advanced Solid Tumors Harboring Mutations in AKT1, AKT2, or AKT3

This study will test the recommended dose of AZD5363 (recommended from a previous phase 1 study of the drug) in patients with specific AKT mutations. In patients who have ER positive breast cancer with an AKT mutation, they will also be receiving a standard breast cancer drug called fulvestrant that is given as an injection. In patients who have prostate cancer with an AKT mutation, they will also be receiving a standard prostate cancer drug called enzalutamide that is taken orally.

NCT03310541 Breast Cancer Prostate Cancer Advanced Solid Tumors Drug: AZD5363 Drug: Enzalutamide Drug: Fulvestrant

MeSH:Prostatic Neoplasms Neoplasms

HPO:Neoplasm Prostate cancer Prostate neoplasm

condoms) Exclusion Criteria: - ER+ breast cancer patients harboring the AKT1 E17K mutation (patient population tested in MSK IRB# 14-214, study D3610C00001 part E, ClinicalTrials.gov --- E17K ---

3 A Multi-Cohort Phase 2 Dose-Escalation Study of ARQ 092 (Miransertib) in Proteus Syndrome

Study Description: 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 2 will receive miransertib at the starting dose of 15 mg/m^2 QD for the first three cycles, and then the dose will be increased to 25 mg/m^2 QD, 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^2 QD. 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. Objectives: Primary Objective: To determine the response to treatment with miransertib as measured by the relative growth of plantar CCTN in participants with Proteus syndrome. Secondary Objectives: - To estimate the change from baseline in pain in participants treated with miransertib - To estimate change from baseline in physical functioning in participants treated with miransertib - To estimate change from baseline in quality of life in participants treated with miransertib - To describe the long-term tolerability and safety of miransertib. - To determine the duration of response in responders with respect to the primary study endpoint Exploratory Objectives: - To describe the effect of miransertib on Proteus syndrome-related overgrowth manifestations assessed by imaging - To describe the effect of miransertib on selected CTCAE categorized Proteus syndrome-related symptoms - To describe the effect of miransertib on d-dimer and fibrinogen levels - To describe the PK profile of miransertib - To describe tolerability and safety of miransertib in participants who previously were treated with miransertib - To describe the effect of miransertib on the rate of growth of the CCTN lesion as compared to historical data from untreated participants - To describe the effect of miransertib on the rate of growth of the total lesional area (CCTN and confluent papules and nodules (pre-CCTN)) as compared to historical data from untreated participants - To determine if the clinical gestalt status of participants with Proteus syndrome improves on/after treatment with miransertib by comparing baseline pre-treatment gestalt to available gestalt data on/after treatment (N of 1 design). Endpoints: Primary Endpoint (assessed in Cohort 1): Change in relative lesional size from baseline will be used to classify each participant as either a responder or non-responder (binary) in the treated population. The primary endpoint is response rate (defined as (less than or equal to 5% relative increase from baseline) in the CCTN lesional area relative to the total plantar area as assessed by blinded central photography review. Secondary Endpoints (assessed in Cohorts 1 and 2): - Change from baseline in pain score as assessed by Wong-Baker FACES Pain Rating Scale - Change from baseline in physical functioning as assessed by PROMIS (Pediatric Upper Extremity Short Form 8a, Parent Proxy Upper Extremity Short Form 8a, Pediatric Mobility Short Form 8a, Parent Proxy Mobility Short Form 8a, Physical Function Short Form 8b, Parent Proxy Pain Behavior Short Form 8a) - Change from baseline in quality of life as assessed by the Pediatric Quality of Life Inventory (PedsQL) - Time from response to relative growth of plantar CCTN greater than or equal to 5% from baseline - Safety and tolerability as assessed by frequency, duration and severity of AEs from the first dose of miransertib through 30 days after the last dose of the drug (severity of AEs will be assessed by current CTCAE version) Exploratory Endpoints (assessed in Cohorts 1 and 2): - Change from baseline in selected disease-related manifestations as evaluated by DXA, CT, MRI, ultrasound, and/or photography - Change from baseline in severity of selected clinical manifestations as assessed by current CTCAE version (participant-specific disease- related symptoms, pre-identified by the Investigator) - Change from baseline in plasma levels of d-dimer and fibrinogen - PK parameters (e.g., maximum plasma drug concen...

NCT04316546 Proteus Syndrome Drug: Miransertib (ARQ092)

MeSH:Proteus Infections Proteus Syndrome Syndrome

- 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 Proteus Syndrome Proteus Infections Proteus Syndrome Syndrome 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. --- Glu17Lys ---

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