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

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Drug: nab-sirolimus

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).

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Torrance, California, United States, 90502
      • Harbor-UCLA Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nab-Sirolimus Dose Cohort 1; 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)	Drug: nab-sirolimus; nab-sirolimus is an mTOR inhibitor; Other Names: ABI-009, nab-rapamycin
Experimental: Nab-Sirolimus Dose Cohort 2; 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)	Drug: nab-sirolimus; nab-sirolimus is an mTOR inhibitor; Other Names: ABI-009, nab-rapamycin
Experimental: Nab-Sirolimus Dose Cohort 3; 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)	Drug: nab-sirolimus; nab-sirolimus is an mTOR inhibitor; Other Names: ABI-009, nab-rapamycin
Experimental: Nab-Sirolimus Dose Cohort 4; 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)	Drug: nab-sirolimus; nab-sirolimus is an mTOR inhibitor; Other Names: ABI-009, nab-rapamycin
Experimental: Nab-Sirolimus Dose Cohort 5; 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)	Drug: nab-sirolimus; nab-sirolimus is an mTOR inhibitor; Other Names: ABI-009, nab-rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting Toxicities	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.	16 weeks

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Aadi Bioscience, Inc.
• Investigators: Principal Investigator: Marc Simon, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2017
• Primary Completion (Actual): August 16, 2022
• Study Completion (Actual): September 16, 2022

Study Registration Dates

• First Submitted: October 23, 2015
• First Submitted That Met QC Criteria: October 26, 2015
• First Posted (Estimated): October 27, 2015

Study Record Updates

• Last Update Posted (Actual): November 25, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Pulmonary Arterial Hypertension; Hypertension; Hypertension, Pulmonary; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Sirolimus
• Other Study ID Numbers: PAH-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No