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

Phase 1

Completed

Conditions: Pulmonary Hypertension

Interventions: Drug: nab-sirolimus

Registration Number: NCT02587325

Lead Sponsor: Aadi Bioscience, Inc.

Brief 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. nab-Sirolimus (also known as ABI-009, nab-rapamycin) is an albumin-bound mTOR inhibitor with improved penetration in lung tissue.

Detailed Description: nab-Sirolimus, an mTOR inhibitor, is a novel formulation of albumin-bound sirolimus nanoparticles and has produced encouraging results in oncology at doses up to 100 mg/m2 given once weekly IV. This study is aimed to determine the optimal clinial dose of once weekly IV nab-sirolimus in patients with PAH and safety of 16 weeks of therapy (Phase 1, Dose finding Safety Part) followed optionally by up to 32 weeks of therapy (Extension Part).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Nab-Sirolimus Dose Cohort 4	nab-sirolimus	nab-Sirolimus Dose Cohort 4 at 5.0 mg/m2, given once weekly intravenously for 16 weeks. The initial 16-Week treatment was followed optionally by up to 32 weeks of therapy (Extension Part)
Nab-Sirolimus Dose Cohort 5	nab-sirolimus	nab-Sirolimus Dose Cohort 5 at 7.5 mg/m2, given once weekly intravenously for 16 weeks. The initial 16-Week treatment was followed optionally by up to 32 weeks of therapy (Extension Part)
Nab-Sirolimus Dose Cohort 1	nab-sirolimus	nab-Sirolimus Dose Cohort 1 at 10 mg/m2, given once weekly intravenously for 16 weeks. The initial 16-Week treatment was followed optionally by up to 32 weeks of therapy (Extension Part)
Nab-Sirolimus Dose Cohort 2	nab-sirolimus	nab-Sirolimus Dose Cohort 2 at 1.0 mg/m2, given once weekly intravenously for 16 weeks. The initial 16-Week treatment was followed optionally by up to 32 weeks of therapy (Extension Part)
Nab-Sirolimus Dose Cohort 3	nab-sirolimus	nab-Sirolimus Dose Cohort 3 at 2.5 mg/m2, given once weekly intravenously for 16 weeks. The initial 16-Week treatment was followed optionally by up to 32 weeks of therapy (Extension Part)

Primary Outcome Measures

Name	Time	Method
Dose-limiting Toxicities	16 weeks	A dose-limiting toxicity (DLT) was defined as a study drug-related Grade ≥3 hematologic AE or persistent intolerable nonhematologic AE of any grade that occurred during the first 4 weeks of treatment, requiring dose reduction or permanent discontinuation of the study drug, in the opinion of the Investigator. The number and percent of patients with a DLT were to be reported by dose cohorts in the Phase 1 dose finding part of the study if any were observed in the study.

Secondary Outcome Measures

Name	Time	Method
Right Heart Catheterization Based on Central Lab Analysis (Pulmonary Vascular Resistance, Cardiac Output, Cardiac Index, Stroke Volume)	17 Weeks	Median Percent Change from Baseline to Week 17 (after 16 weeks of treatment) in RHC based on Central Lab Analysis (Pulmonary vascular resistance, Cardiac Output, Cardiac Index, Stroke Volume)
6-minute Walk Distance (6MWD)	17 Weeks	Median Percent Change from Baseline to Week 17 (after 16 weeks of treatment) in 6MWD
N-terminal Pro-brain Natriuretic Peptide (NT Pro-BNP)	17 Weeks	Median Percent Change from Baseline to Week 17 (after 16 weeks of treatment) in NT Pro-BNP

Trial Locations

Locations (6): Harbor-UCLA Medical Center
🇺🇸
Torrance, California, United States
Indiana University
🇺🇸
Indianapolis, Indiana, United States
National Institutes of Health
🇺🇸
Bethesda, Maryland, United States
University of Pittsburgh Medical Center
🇺🇸
Pittsburgh, Pennsylvania, United States
Inova Fairfax Hospital
🇺🇸
Falls Church, Virginia, United States
University of Arizona
🇺🇸
Tucson, Arizona, United States