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

Study Overview
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Brief Summary
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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.

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

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: nab-sirolimus (also known as ABI-009, nab-rapamycin, albumin-bound rapamycin)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nab-sirolimus (also known as ABI-009, nab-rapamycin, albumin-bound rapamycin)<br> | Drug: nab-sirolimus (also known as ABI-009, nab-rapamycin, albumin-bound rapamycin)<br>* ABI-009<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD | Maximum-Tolerated Dose | 16 weeks | 
| DLT | Dose-limiting toxicities | 16 weeks |