Phase 1/1b Study With Nab-sirolimus for Patients With Severe Pulmonary Arterial Hypertension

Pulmonary Hypertension Clinical Trial

Official title:

A Phase 1/1b Clinical Trial of ABI-009, an mTOR Inhibitor, for Patients With Severe Pulmonary Arterial Hypertension (PAH)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02587325
• Other study ID #: PAH-001
• Status: Completed
• Phase: Phase 1
• Start date: April 1, 2017
• Est. completion date: September 16, 2022

Study information

• Verified date: January 2023
• Source: Aadi Bioscience, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

mTOR activation has been shown to be relevant in the development and progression of pulmonary hypertension. Inhibition of mTOR has been shown to reverse or regress pulmonary hypertension in animal models. ABI-009 is an albumin-bound mTOR inhibitor with improved penetration in lung tissue.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: September 16, 2022
• Est. primary completion date: August 16, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female age >18 years old with a current diagnosis of WHO Group 1 PAH including idiopathic pulmonary arterial hypertension (IPAH), heritable pulmonary arterial hypertension (HPAH), drug and toxin induced PAH, or PAH associated with connective tissue disease, or congenital heart defects (repaired greater than 1 year prior to Screening)

• Must meet following hemodynamic definition prior to initiation of study drug

• Mean PAP of = 25 mm Hg

• PCWP or left ventricular end diastolic pressure (LVEDP) of = 15 mm

• PVR > 5 mmHg/L/min (Woods unit)

• Functional class II or III according to the WHO set forth at the Dana Point Classification 2008 Meeting

• On 2 or more specific standard PAH therapies (for = 8 consecutive weeks and at stable dose for = 4 consecutive weeks) unless documented inability to tolerate 2 standard therapies

• Meet the following criteria determined by pulmonary function tests completed no more than 24 weeks prior to screening, performed with or without bronchodilation:

• Forced expiratory volume in one second (FEV1) = 55% of predicted normal

• FEV1:forced vital capacity (FVC) ratio = 0.60

• 6MWD =150 meters and =450 meters

• Negative serum pregnancy test

• Female of childbearing age either surgically sterilized or using acceptable method of contraception

• Ability to provide written informed consent by the patient or legal guardian

Exclusion criteria:

• History of heart disease including left ventricular ejection fraction (LVEF) = 40% or clinically significant valvular constrictive or atherosclerotic heart disease (myocardial infarction, angina, cerebrovascular accident)

• History of malignancy in 2 years prior to enrollment

• Pulmonary hypertension (PH) belonging to groups 2 to 5 of the 2013 Nice classification

• Current or recent (< 3 months) use of inotropic or vasopressor agents for the treatment of PAH

• Recent (< 2 months) PAH related hospital admission

• History of allergic reactions attributed to compounds of similar chemical or biologic composition including macrolide (eg, azithromycin, clarithromycin, dirithromycin, and erythromycin) and ketolide antibiotics

• Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy

• Uncontrolled hyperlipidemia (serum triglyceride =300 mg/dL)

• Serum cholesterol =350 mg/dL

• Surgery within 3 months of start date of study drug

• Baseline cytopenias:

• Absolute Neutrophil Count = 1.5 x 109/L

• Hemoglobin = 9 g/dL

• Platelet count < 100,000/mm3

• Baseline liver disease: ALT/AST, total bilirubin, alkaline phosphatase >1.5 x ULN

• Baseline renal disease: creatinine >1.5 ULN and/or creatinine clearance (Cockcroft formula) = 30 mL/min

• Inability to attend scheduled clinic visits

• Prior use of study drug within previous 6 months from enrollment

• Previous lung transplant

• Naïve to available standard PAH therapy

• Concomitant genetic or acquired immunosuppressive diseases (such as HIV, AIDS)

• Uncontrolled intercurrent illness that in the opinion of the investigator would limit compliance and tolerance to study requirements (eg, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, uncontrolled hypertension, coronary artery disease, or psychiatric illness/social situations)

• Concomitant enrollment in another investigational treatment protocol for PAH

• Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to receiving the first dose of ABI-009. Additionally, use of any known CYP3A4 substrates with narrow therapeutic window (such as fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, terfanide) within the 14 days prior to receiving the first dose of ABI-009

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Arterial Hypertension
• Pulmonary Hypertension

Intervention

Drug:
• nab-sirolimus (also known as ABI-009, nab-rapamycin, albumin-bound rapamycin)
ABI-009

Locations

Country	Name	City	State
United States	National Institutes of Health	Bethesda	Maryland
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Indiana University	Indianapolis	Indiana
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Harbor-UCLA Medical Center	Torrance	California
United States	University of Arizona	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Aadi Bioscience, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTD	Maximum-Tolerated Dose	16 weeks
Primary	DLT	Dose-limiting toxicities	16 weeks