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

NCT02587325 | Completed Phase 1 Results FDA Drug

• 1 other identifier: PAH-001
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 6

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.

Conditions

Pulmonary Hypertension

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Right Heart Catheterization Based on Central Lab Analysis (Pulmonary Vascular Resistance, Cardiac Output, Cardiac Index, Stroke Volume)

  17 Weeks

• 6-minute Walk Distance (6MWD)

  17 Weeks

• N-terminal Pro-brain Natriuretic Peptide (NT Pro-BNP)

  17 Weeks

Study Arms (5)

Nab-Sirolimus Dose Cohort 1

EXPERIMENTAL

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 Dose Cohort 2

EXPERIMENTAL

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 Dose Cohort 3

EXPERIMENTAL

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 Dose Cohort 4

EXPERIMENTAL

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 Dose Cohort 5

EXPERIMENTAL

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

Interventions

nab-sirolimus DRUG

nab-sirolimus is an mTOR inhibitor

Also known as: ABI-009, nab-rapamycin

Nab-Sirolimus Dose Cohort 1; Nab-Sirolimus Dose Cohort 2; Nab-Sirolimus Dose Cohort 3; Nab-Sirolimus Dose Cohort 4; Nab-Sirolimus Dose Cohort 5

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• MWD ≥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

You may not qualify if:

• 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

Sponsors & Collaborators

• Aadi Bioscience, Inc.: lead

Study Sites (6)

University of Arizona

Tucson, Arizona, 85724, United States

Location

Harbor-UCLA Medical Center

Torrance, California, 90502, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

National Institutes of Health

Bethesda, Maryland, 20892, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Inova Fairfax Hospital

Falls Church, Virginia, 22042, United States

Location

MeSH Terms

Conditions

Hypertension, Pulmonary

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Limitations and Caveats

The originally planned dose levels started at 10 mg/m2 weekly nab-sirolimus. While there were no DLTs at the initial dose level (n = 4), based on the totality of AEs and dose reductions, dose levels were modified and patients sequentially enrolled at 1.0, 2.5, 5.0, and 7.5 mg/m2. Given the difficulties with enrollment during the COVID-19 pandemic, the study closed prior to fully enrolling at the last dose level of 7.5 mg/m2 and thus, no Phase 1b cohort expansion occurred at this dose.

Results Point of Contact

• Title: Aadi Medical Information
• Organization: Aadi Bioscience, Inc.

MedInfo@aadibio.com

1-888-246-2234

Study Officials

• Marc Simon, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 23, 2015
• First Posted: October 27, 2015
• Study Start: April 1, 2017
• Primary Completion: August 16, 2022
• Study Completion: September 16, 2022
• Last Updated: November 25, 2024
• Results First Posted: November 25, 2024

Record last verified: 2024-10

Locations

US (6)