Clinical trial NCT02587325
Conditions: Pulmonary Hypertension
Sponsor: Aadi Bioscience, Inc.
Start date: 2017-04-01; Completion date: 2022-09-16
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

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).

Arms: arm 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) arm 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) arm 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) arm 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) arm 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)
Interventions: intervention 1: nab-sirolimus
Intervention descriptions: intervention 1: nab-sirolimus is an mTOR inhibitor

Protocol documents:
Prot_SAP_000.pdf: 
 
Cover Page 
 
Study PAH-001, NCT02587325 
 
Protocol Including Statistical Analysis 
 
Last Approved Version 4.0 
Date: October 24, 2019 
 
Protocol Title 
A phase 1/1b clinical trial of ABI-009, an mTOR inhibitor, for 
patients with pulmonary arterial hypertension (PAH) 
 


ABI-009 
Protocol: PAH-001 
 
Aadi Bioscience 
Confidential and Proprietary 
1 
Amendment: October 24, 2019 
 
 
 
A phase 1/1b clinical trial of ABI-009, an mTOR inhibitor, for patients 
with pulmonary arterial hypertension (PAH) 
 
INVESTIGATIONAL PRODUCT (IP): 
 
ABI-009 
PROTOCOL NUMBER: 
 
PAH-001 
VERSION HISTROY: 
 
 
Original: 
 
December 10, 2015  
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
 
April 25, 2016 
October 27, 2017 
September 9, 2018 
October 24, 2019 
IND NUMBER: 
 
128090   
SPONSOR NAME/ ADDRESS: 
 
 
 
Aadi Bioscience, Inc. 
17383 Sunset Blvd., Suite A250 
Pacific Palisades 
CA 90272 
 
 
 
 
 
 
CONFIDENTIAL 
This protocol is provided to you as an Investigator, potential 
Investigator, or consultant for review by you, your staff, and ethics 
committee/institutional review board.  The information contained in 
this document is regarded as confidential and, except to the extent 
necessary to obtain informed consent, may not be disclosed to 
another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must 
be informed that the information is confidential and may not be 
further disclosed by them. 


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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION  
 
 
 


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Aadi OFFICIAL SIGNATURE PAGE 




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PROTOCOL SYNOPSIS 
Investigational 
Product (IP) 
 
ABI-009, sirolimus albumin-bound nanoparticles for injectable 
suspension, nab-sirolimus, formerly nab-rapamycin  
Study Title 
A phase 1/1b dose-finding clinical trial evaluating the safety of ABI-009 
as antiproliferative therapy for patients with pulmonary arterial 
hypertension (PAH) 
Protocol Number 
PAH-001 
Phase 
1 
Indication 
Intravenous (IV) ABI-009 as antiproliferative therapy for patients with 
pulmonary arterial hypertension (PAH). The patient population is adults 
with PAH (World Health Organization [WHO] Function Class II and III), 
a subset of patients known to have a poor prognosis and worse 
survival.  
Study Objectives 
Objectives 
This phase 1/1b study will involve dose escalation to determine the 
maximum tolerated dose (MTD) and safety of 16 weeks of therapy 
(Dose-finding Safety Part) followed optionally by up to 32 additional 
weeks of therapy (Extension Part) with ABI-009 IV in patients with PAH 
who are WHO Functional Class II or III despite best available 
background therapy. The MTD will be determined on the basis of the 
results from the safety evaluation.  
After the MTD is reached in phase 1, there will be up to 2 cohort 
expansions in phase 1b at the MTD and/or one alternate dose or 
schedule to determine the recommended phase 2 dose. The expanded 
cohorts will be such that up to 10 patients for each of the cohorts will 
be enrolled to obtain additional safety and efficacy data, inclusive of 
patients from phase 1. The recommended phase 2 dose, which may 
differ from the MTD, will be determined on the basis of results from 
safety, efficacy, pharmacologic and correlative studies in this phase 
1/1b study. 
Exploratory Objectives  
• To evaluate pharmacokinetic information that may be correlated 
with safety and/or efficacy observations.  
Study Endpoints 
Endpoints 
Primary Endpoints  
• MTD, dose-limiting toxicities (DLT, defined in 7.2.1), and safety 
profile of 16 weeks of ABI-009 given IV.  


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• Safety profile of the up to 48 weeks of treatment 
 
Secondary Endpoints 
The following will be measured before treatment at baseline and at 
week 17 (after 16 weeks of treatment in the Dose-finding Safety Part): 
• pulmonary 
vascular 
resistance 
(PVR) 
by 
right 
heart 
catheterization 
• pulmonary artery pressure (PAP) 
• pulmonary capillary wedge pressure (PCWP) 
• central venous pressure (CVP)  
The following will be measured at baseline, 5, 9, 13, and 17 weeks: 
• Doppler-echocardiographic assessments of right ventricular 
structure and function 
• 6-minute walk distance (6MWD) 
• WHO functional class  
• Pulmonary function test 
The following will be measured at every 8 weeks during the additional 
32 weeks of the Extension Part (ie, at week E9, E17, E25, and E33): 
• 6MWD  
• WHO Functional Class 
• Pulmonary function test 
 
Exploratory Endpoints 
• Pharmacokinetic (PK) profile and trough level of sirolimus for 
weekly treatment during the 16 weeks of Dose-finding Safety 
Part and every other week treatment during the Extension Part 
• Measurement of brain naturetic peptide (BNP), C-reactive 
protein (CRP) and troponin levels, indicative of right ventricular 
strain, at baseline, 5, 9, 13, and 17 weeks, and for BNP, every 8 
weeks in the optional Extension Part (E9, E17, E25, E33) 
• Change from baseline to week 17, and to weeks E17 and E33 in 
the Extension Part in 36-Item Short Form Health Survey (SF-36) 
physical functioning scale 
• Change from baseline to week 17, and to weeks E17 and E33 in 
the Extension Part in emPHasis10 questionnaire 


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STUDY DESIGN  
This study is a prospective phase 1/1b, single arm, open-label, multi-
institutional study to determine the MTD, safety, and preliminary 
efficacy of IV ABI-009 in patients with PAH.  
Patients who, in the opinion of the investigator and Safety Committee, 
tolerate ABI-009 well and achieve clinical benefit during the first 16-
week treatment (Dose-finding Safety Part), and for whom there are no 
alternative therapies available, may opt to continue therapy for an 
additional 32 weeks at their assigned dose or lower, if permanently 
reduced (optional Extension Part). The Extension Part should start 
within 4 weeks after the last dose of the 16-week Dose-finding Safety 
Part. 
The study will be conducted in compliance with International 
Conference on Harmonisation (ICH) Good Clinical Practices (GCPs). 
 
Sample Size 
Phase 1: Up to 24 patients will be enrolled using the standard 3+3 dose 
escalation design in the dose-finding phase. 
Phase 1/b:  Additional 4-7 patients will be enrolled in up to 2 expansion 
cohorts to obtain a total of 10 patients at each of the 2 dose levels 
(inclusive of patients from phase 1), the MTD and/or an alternate dose 
or schedule. 
Study Population 
Patients with PAH (WHO Functional Class II or III) in spite of 2 or more 
standard PAH therapies, assessed locally in each institution for 
enrollment. 


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Inclusion Criteria 
1) 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) 
2) Must meet following hemodynamic definition prior to initiation of 
study drug 
a. Mean PAP of ≥25 mmHg 
b. PCWP or left ventricular end diastolic pressure (LVEDP) of 
≤15 mm 
c. PVR >5 mmHg/L/min (Woods unit) 
3) Functional class II or III according to the WHO set forth at the Dana 
Point Classification 2008 Meeting 
4) 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    
5) Meet the following criteria determined by pulmonary function tests 
completed at screening: 
a. Forced expiratory volume in one second (FEV1) ≥55% of 
predicted normal   
b. FEV1: forced vital capacity (FVC) ratio ≥0.60 
6) 6MWD ≥150 meters and ≤450 meters 
7) Male or non-pregnant and non-breast feeding female:  
• Females of child-bearing potential must agree to use effective 
contraception without interruption from 28 days prior to starting 
IP and while on study medication and have a negative serum 
pregnancy test (β-hCG) result at screening and agree to 
ongoing pregnancy testing during the course of the study, and 
after the end of study treatment. A second form of birth control 
is required even if she has had a tubal ligation.  
• Male patients must practice abstinence or agree to use a 
condom during sexual contact with a pregnant female or a 
female of childbearing potential while participating in the study. 
A second form of birth control is required even if he has 
undergone a successful vasectomy.  
8) Ability to provide written informed consent by the patient or legal 
guardian 
Exclusion Criteria 
1) 
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) 
2) 
History of malignancy in 2 years prior to enrollment 
3) 
Pulmonary hypertension (PH) belonging to groups 2 to 5 of the 
2013 Nice classification 


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4) 
Current or recent (<3 months) use of intravenous inotropic or 
vasopressor agents for the treatment of PAH 
5) 
Recent (<2 months) PAH-related hospital admission 
6) 
History of allergic reactions attributed to compounds of similar 
chemical or biologic composition including macrolide (eg, 
azithromycin, clarithromycin, dirithromycin, and erythromycin) and 
ketolide antibiotics 
7) 
Uncontrolled diabetes mellitus as defined by HbA1c >8% despite 
adequate therapy 
8) 
Uncontrolled hyperlipidemia (serum triglyceride ≥300 mg/dL) 
9) 
Serum cholesterol ≥350 mg/dL 
10) Surgery within 3 months of start date of study drug 
11) Baseline cytopenias: 
a.  Absolute Neutrophil Count ≤1.5 x 109/L 
b. Hemoglobin ≤9 g/dL 
c. Platelet count ≤100,000/mm3 
12) Baseline liver disease: ALT/AST, total bilirubin, alkaline 
phosphatase ≥1.5 x ULN 
13) Creatinine clearance (Cockroft formula) ≤30 mL/min  
14) Inability to attend scheduled clinic visits 
15) Prior use of an mTOR inhibitor within previous 6 months from 
enrollment 
16) Previous lung transplant 
17) Known Human Immunodeficiency Virus (HIV) 
18) Active Hepatitis B or Hepatitis C  
19) 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) 
20) Concomitant enrollment in another investigational treatment 
protocol for PAH  
21) 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 
Length of Study  
The study is expected to take approximately 30 months from first 
patient enrolled to last patient follow-up, including approximately 18 
months of enrollment period, up to 16 weeks of Dose-finding Safety  
Part (or until treatment is not tolerated), , followed by an optional 
Extension Part for up to 32 weeks, and at least 28 days follow-up after 


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the last dose either in the Dose-finding Safety or Extension Part, 
whichever is later.  
The End of Study (EOS) defined as either the date of the last visit of 
the last patient to complete the study, or the date of receipt of the last 
data point from the last patient that is required for primary, secondary, 
and/or exploratory analysis, as pre-specified in the protocol.  
End of Treatment is defined as the date of the last dose of ABI-009. 
End of Treatment Visit is when efficacy and safety assessments and 
procedures are performed after the last treatment. 
•
For a patient who does not complete the 16-week treatment,
EOT Visit must occur within 4 weeks (±7 days) after the last
dose of ABI-009.
•
For patients who complete the 16-week treatment, the final
efficacy and safety assessments and procedures (EOT Visit) are
performed at week 17.
Follow-up period is the on-study time period for at least 28 days after 
the last treatment either in the Dose-finding Safety Part or optional 
Extension Part, whichever is later. All patients that discontinue study 
drug and have not withdrawn full consent to participate in the study will 
continue in the follow-up phase for survival and therapy. Follow up will 
continue up to 1 year, approximately every 12 weeks (±3 weeks), until 
withdrawal of consent, or the study closes, whichever is the earliest. 
This evaluation may be made by record review and/or telephone 
contact. 
Study Treatments 
This phase 1/1b study will have a 16-week Dose-finding Safety Part to 
identify recommended phase 2 dose and evaluate the safety and 
efficacy profile of weekly ABI-009 (via dose-finding and dose-expansion 
cohorts), followed by an optional 32-week Extension Part to obtain 
additional safety and efficacy data on longer term treatment with ABI-
009.   
16 weeks of Dose-finding Safety Part 
In the dose-finding phase 1 portion of the study, 4 dose levels of ABI-
009 will be tested in cohorts of 3 patients each (1, 2.5, 5, and 7.5 mg/m2, 
see Table 1), using the 3+3 dose escalation design. There will be no 
intra-patient dose escalation allowed. Escalation to the next dose level 
with a new cohort of 3 patients will occur after no DLT was observed in 
the first treatment cycle of 4 weeks. If a DLT occurs in a cohort, 
additional 3 patients will be recruited to the cohort. If no further DLTs 
occur, then a new cohort of 3 patients at the next higher dose level can 
be enrolled. If 2/6 patients at dose level 1a experience a DLT, then that 
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terminated. If 2/6 patients at dose levels 2a, 3a, or 4a experience a 
DLT, then the previous dose level is considered the MTD.   
It is estimated that a maximum of up to 24 patients will be required to 
achieve the MTD; however, MTD could be reached with as few as 9 
patients. Patients will be allowed to dose reduce by one dose level for 
reasons of toxicity, with a maximum of 2 dose reductions allowed for a 
patient. At the lowest dose level, a dose reduction of 25% will be 
allowed. 
Table 1: Doses of ABI-009 Given Weekly 
Dose Level 
1a 
2a 
3a 
4a 
ABI-009 Weekly Dose 
(mg/m2) 
1 
2.5 
5 
7.5 
Note: The original protocol (dated December 10, 2015) included 
dose levels 1 (10 mg/m2), 2, (20 mg/m2) and 3 (30 mg/m2), and 
dose level -1 (5 mg/m2). 
After the MTD is reached, in phase 1b, there may be up to 2 cohort 
expansions at the MTD and/or one alternate dose or schedule to 
determine the recommended phase 2 dose. 
Optional 32-week Extension Part 
Patients who, in the opinion of the investigator and Safety Committee, 
tolerate ABI-009 well and achieve clinical benefit during the Dose-
finding Safety Part, and for whom there are no alternative therapies 
available, may opt to continue therapy (optional Extension Part) for up 
to an additional 32 weeks at their assigned dose or lower, if 
permanently reduced. The optional Extension Part should start within 4 
weeks after the last dose of the 16-week Dose-finding Safety Part.  
Key Safety 
Assessments 
Overview of Key Safety Assessments During Dose-finding Safety 
and Optional Extension Part 
Physical exam including a complete set of vital signs and clinical 
laboratory monitoring will be conducted weekly on the day of drug 
infusion. Patients will be closely monitored for adverse events (AEs). 
Safety and tolerability will be monitored through continuous reporting of 
treatment-emergent and treatment-related AEs, AEs of special interest 
(identified based on previous experience in a similar population), 
laboratory abnormalities, and incidence of patients experiencing dose 
modifications, dose delay/dose not given, dose interruptions, and/or 
premature discontinuation of IP due to an AE. All AEs will be recorded 
by the investigator from the time the patient signs informed consent 


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until 28 days after the last dose of IP and those serious adverse events 
(SAEs) made known to the investigator at any time thereafter that are 
suspected of being related to IP. Toxicities will be graded by National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAEs) v4.1. 
Physical examination, vital sign, laboratory assessments (eg, serum 
chemistry, hematology) will be monitored. All SAEs (regardless of 
relationship to ABI-009) will be followed until resolution. Laboratory 
analysis will be performed as per study schedule.  
Key Efficacy 
Assessments 
Overview of Key Efficacy Assessments During the 16-week Dose-
finding Safety Part 
The following will be measured before treatment at baseline and at 17 
weeks (after 16 weeks of treatment in the Dose-finding Safety Part): 
•
PVR by right heart catheterization
•
PAP
•
PCWP
•
CVP
The following will be measured at baseline, 5, 9, 13, and 17 weeks: 
•
Doppler-echocardiographic assessments of right ventricular
structure and function
•
6MWD
•
Pulmonary function test
Overview of Key Efficacy Assessments During the Optional 
Extension Part 
The following will be measured every 8 weeks form the start of the 
Extension Part (ie, at week E9, E17, E25, and E33): 
•
6MWD
•
WHO Functional Class
•
Pulmonary function test
Statistical 
Considerations 
The dose-escalation portion of this clinical study will enroll up to 24 
patients. Dose escalation will follow the 3+3 rule to establish the MTD. 
Three planned dose levels are to be used (Table 1). The minimum 
number of patients required to establish the MTD is 9 patients. In case 
there is a dose limiting toxicity at each of the 4 dose levels, each cohort 
of 3 patients will be expanded to 6 patients, in which case a total of 24 
patients will be treated.   


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After the MTD is achieved, up to 2 cohorts (at the MTD and/or one 
alternate dose or schedule) will be expanded to enroll a total of 10 
patients in each cohort to further evaluate safety and preliminary utility 
(potential for clinical efficacy) of ABI-009 in the treatment of PAH.    
 
Safety Analyses: 
The treated population will be the analysis population for all safety 
analyses. Adverse events will be coded using the Medical Dictionary 
for Medical Activities (MedDRA) and grouped by their system organ 
class and preferred term. Summary tables will include the number and 
percentage of patients with treatment-emergent and treatment-related 
AEs, AEs of special interest, SAEs, and incidence of patients 
experiencing dose modifications, dose delay/dose not given, dose 
interruptions, and/or premature discontinuation of IP due to an AE. 
 
 










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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABI-009 
nanoparticle albumin-bound sirolimus 
AE 
Adverse events 
ALT/AST 
alanine aminotransferase / aspartate aminotransferase 
CBC 
complete blood count 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVP 
central venous pressure 
DLT 
dose-limiting toxicity 
EOS 
End of study 
EOT 
end of treatment 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practices 
HPAH 
heritable pulmonary arterial hypertension 
ICH  
International Conference on Harmonisation 
IPAH 
idiopathic pulmonary arterial hypertension 
LVEF 
left ventricular ejection fraction 
MTD 
maximum tolerated dose 
NCI  
National Cancer Institute  
PAH 
pulmonary arterial hypertension 
PAP 
pulmonary artery pressure 
PAVSCM 
pulmonary artery vascular smooth muscle cell 
PCWP 
pulmonary capillary wedge pressure 
PK 
pharmacokinetic 
PVR 
pulmonary vascular resistance 
SAE 
serious adverse events 
SF-36 
36-Item Short Form Health Survey 
ULN 
upper limit of normal 
WHO 
World Health Organization 
6MWD 
6-minute walk distance 
 
 


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1. 
INTRODUCTION 
1.1. 
Pulmonary Arterial Hypertension 
Pulmonary arterial hypertension (PAH) is a rare, debilitating and fatal disease for which 
there is currently no cure. The disease specifically affects the endothelium and smooth 
muscle of the pulmonary arteries, with cellular constriction and hyperproliferation leading 
to vascular remodeling, stiffening, and narrowing. The progressive increase in pulmonary 
vascular resistance (PVR) over time increases right ventricular afterload and leads to right 
ventricular dilation and failure. Progressive reduction in cardiac output from right 
ventricular failure leads to decreased exercise capacity and death [1]. The current FDA 
approved therapies for PAH target vascular factors that regulate vasodilation and 
vasoconstriction and include the prostacyclin analogues, endothelin-1 receptor 
antagonists, phoshodiesterase 5 (PDE-5) inhibitors and soluble guanylate cyclase (sGC) 
stimulators. These agents alone and in combination improve exercise capacity and delay 
the time to clinical worsening but do not significantly prolong survival [2, 3] or specifically 
address the underlying hyperproliferation of the endothelial and smooth muscle cells in 
the pulmonary arteries. 
Recent human clinical trials using the antiproliferative agent imatinib (Novartis), suggests 
that new approaches targeting vascular endothelial and smooth muscle proliferation is an 
efficacious approach for patients with PAH [4]. While imatinib was effective in treating 
PAH, i.e., it significantly decreased PVR and increased 6-minute walking distance 
(6MWD) [4], the clinical development of imatinib was halted by the sponsor (Novartis) for 
high risk of severe toxicity, specifically, subdural hematoma. Therefore, there is a great 
need for new safer ‘antiproliferative’ agents to be evaluated in the treatment of PAH. 
Recent in vitro studies [5, 6], animal models [6, 7], new translational data using human 
PAH patient samples [6] and a clinical case report [8] suggest strongly that rapamycin 
(sirolimus), an allosteric mammalian target of rapamycin (mTOR) inhibitor, can prevent 
and reverse PAH. mTOR signaling is hyperactivated in PAH, and inhibiting this pathway 
is a promising novel treatment approach. mTOR inhibition resulted in strong 
antiproliferative activity, particularly in vascular smooth muscle cells, which was 
demonstrated by Goncharov (2014) [6], Houssaini (2013) [9], and Kyrmskaya et al (2011) 
[5]. In addition, the suppression of mTOR has been described to affect the canonical 
hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), platelet-
derived growth factor (PDGF) and p27 cell cycle pathways, which are known to be central 
to PAH pathogenesis [5, 10, 11]. 
nab-Sirolimus (ABI-009, Aadi, Pacific Palisades, CA) is a novel albumin-bound 
nanoparticle form of sirolimus that has shown excellent antiproliferative activity in tumor 
xenograft models as well as a porcine restenosis model with strong evidence of vascular 
smooth muscle cell suppression and high accumulation in the lung. A recent phase 1 
clinical trial in patients with solid tumors showed evidence of clinical activity, low toxicity, 
and favorable pharmacokinetic (PK) profile [12]. The safety profile of ABI-009, despite 
higher doses, compared very favorably to oral sirolimus and rapalogs in this patient 
population (historical comparison). In this application, we propose the clinical testing of 


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ABI-009, the long acting nanoparticle human albumin-bound formulation of sirolimus, as 
a novel targeted systemic therapy for PAH.  
The significance of this study lies in addressing a debilitating disease with a new 
antiproliferative approach specifically targeting the disease biology.  
Pulmonary arterial hypertension is classified into subgroups including idiopathic PAH 
(IPAH), familial, and PAH associated with other conditions (APAH). Idiopathic PAH 
accounts for at least 40% of PAH cases, 4% are familial type, and the remaining cases 
are APAH (>50%). 
The number of patients with PAH in the US is estimated to be 30,000; however, PAH is 
widely recognized as a disease that is underdiagnosed [13]. Pulmonary arterial 
hypertension has an incidence of 2.4 cases per million people per year, and an estimated 
prevalence of between 15 to 50 cases per million people [14]. The prevalence of PAH in 
certain at-risk groups is substantially higher: in patients with systemic sclerosis it is 7% to 
12% [15, 16]. PAH is considered a complex, multidisciplinary medical condition that, if left 
untreated, can be life threatening with 3-year survival after diagnosis at only about 50%. 
The mean age at diagnosis is 36 years, but PAH can affect people from 20 to 90 years 
old. Women are affected approximately twice as often as men.  
 
Treatment for PAH and the Rationale for using ABI-009 
The FDA has approved several drugs to date for the treatment of PAH, all of which are 
vasodilators and offer only symptomatic relief. The administration routes include oral, 
inhaled, subcutaneous (SC), and intravenous (IV). They belong to 4 classes based on the 
mechanism of action: Prostacyclin derivatives (epoprostenol, iloprost and treprostinil) are 
potent vasodilators; endothelin receptor antagonists (ERAs, eg. bosentan, macitentan 
and ambrisentan) block the binding of endothelin-1 to the receptor and inhibit the 
endothelin effects of vasoconstriction and smooth muscle growth; phosphodiesterase 5 
(PDE-5) inhibitors (sildenafil and tadalafil) block the breakdown of cyclic guanosine 
monophosphate and enhance nitric oxide-mediated vasodilation; and soluble guanylate 
cyclase (sGC) stimulators (riociguat). 
These current approved PAH therapeutics mainly function as vasodilators and do not 
address the endothelial and smooth muscle cell hyperproliferation aspect of the disease. 
Thus, an entire aspect of the biology of this disease has not been effectively explored. 
Importantly, current treatments provide largely symptomatic relief with temporary 
improvements in right heart function and exercise capacity; invariably PAH patients’ 
disease progresses, even on combination therapy. The use of ABI-009 as a safe, 
efficacious and targeted anti-proliferative therapy represents a unique opportunity to help 
patients with debilitating PAH, already on maximal approved therapy, with the possibility 
of modifying the course of the disease. An effective treatment could have a large clinical 
impact on the lives of these patients. 
Imatinib, a tyrosine kinase inhibitor targeting PDGF, Bcr/Abl and c-Kit, is the only 
antiproliferative drug that has been tested in PAH in late-stage clinical trials. In a phase 3 
study, imatinib demonstrated efficacy, meeting the efficacy endpoints of improved 6MWD 


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and reduction in PVR, but an increase in unexpected rates of intracranial bleeding and 
high dropout rates due to AEs have led the sponsor (Novartis) to stop development of this 
drug [4]. These studies provide proof of principle that a vascular remodeling anti-
proliferative agent can be efficacious in PAH patients, however, safety remains the key 
issue for such approaches. 
This study will present a unique opportunity to develop a targeted molecular 
antiproliferative therapy for PAH. Recent evidence strongly suggests that the mTOR 
pathway is important in PAH development [5, 6], and sirolimus is efficacious in models of 
PAH [7, 8]. Systemic (IV) ABI-009, exhibits preferential lung uptake [17] with a favorable 
PK profile for PAH (unlike oral mTOR agents) and a favorable safety profile in a human 
phase 1 oncology trial [12]. 
 
1.2. 
ABI-009 Background 
1.2.1. 
Rapamycin (Sirolimus) and Rapalogs 
Sirolimus is a crystalline powder with the empirical formula C51H79NO13 and a molecular 
weight of 914.17. Sirolimus is a protein kinase inhibitor that is used for 
immunosuppression in transplant patients and is under investigation as a cancer 
treatment. Sirolimus inhibits the mammalian target of rapamycin (mTOR), a regulatory 
protein kinase in cancer that recognizes high stress levels, including depleted nutrient 
levels and states of hypoxia [18]. mTOR is a serine/threonine-specific protein kinase, 
downstream of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) pathway, 
and a key regulator of cell survival, proliferation, stress, and metabolism. Additionally, 
mTOR is involved in regulating angiogenesis by controlling endothelial and smooth 
muscle cell proliferation via the hypoxia-inducible factor-1α and vascular endothelial 
growth factor [19]. Consistent with its role in cell proliferation, the mTOR pathway is 
frequently overactivated in a number of human malignancies and is thus considered to 
be an attractive target for anti-cancer therapy. Sirolimus and its analogs (rapalogs) 
function as allosteric inhibitors of mTORC1 and are currently used in the treatment of 
advanced renal cell carcinoma and other tumors [20]. 
1.2.2. 
ABI-009 (nab-Sirolimus) 
The nanoparticle albumin-bound sirolimus (nab-sirolimus, ABI-009) is freely dispersible 
in saline and is suitable for intravenous administration and have produced favorable 
safety profile and produced evidence of efficacy in patients with metastatic solid tumors 
[12]. 
The nanoparticle albumin-bound or nab® technology (Abraxis BioScience, a wholly-
owned subsidiary of Celgene Corporation) when applied to hydrophobic molecules, such 
as paclitaxel (nab-paclitaxel; Abraxane®), has led to improved drug delivery, safety, and 
efficacy in various solid tumors compared with the conventional paclitaxel formulation 
[21]. This suggests that a nab formulation of sirolimus may also produce similar 
advantages over the standard sirolimus. 


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1.2.3. 
ABI-009, Albumin Mechanism of Transport and Selectivity for PAH 
Pathology 
The nab technology utilizes albumin receptor-mediated (gp60) caveolar endothelial 
transcytosis to transport dugs to the subendothelium [22]. Indeed, we have seen in our 
laboratory that nab-drug transcytosis across the epithelial monolayer was dependent on 
albumin and caveolae formation [22]. Albumin is highly soluble, has long plasma half-life 
and broad binding affinity, and highly accumulated in disease sites such as tumors and 
during inflammation [23, 24], making it an ideal candidate for drug delivery. Consequently, 
the hyperproliferative and leaky vasculature in tumors resulted in increased albumin-
based drug uptake for nab-drugs [25]. Increased gp60 expression and robust albumin 
uptake has been observed in rat lung tissues and wild-type mice endothelial cells of aorta 
relative to other tissues [26-28]. Mechanical stress as well as mediators such as cytokines 
and thrombin, a key player in the pathobiology of PAH, can mediate morphological 
changes in endothelial cells and widening of the intercellular junctions [29, 30]. PAH is 
associated with increased transendothelial permeability of macromolecules and lung 
edema, which contains high level albumin protein [24, 31]. It has been further observed 
that cells under stress, such as those in tumors and sites of inflammation, display 
significant higher albumin uptake than normal cells and degrade albumin for their nutrient 
and energy needs [23, 32, 33]. Accumulating evidence shows that PAVSM and 
endothelial cells in PAH share several analogous features with cancer cell stress 
response, such as increased proliferation and resistance to apoptosis [6, 34-37], 
association with metabolic glycolytic shift, deregulated mitochondrial function, and 
constitutive up-regulation of HIF1alpha [6, 36, 38]. Taken together, these results provide 
strong background that the hyperproliferative vascular lesions in PAH should result in 
enhanced uptake of albumin-bound sirolimus over oral sirolimus and that anti-proliferative 
strategies used in cancer are relevant to treat PAH.   
1.2.3.1. 
Preclinical Studies with ABI-009 
In preclinical studies, ABI-009 has shown an excellent safety and efficacy profile; it 
showed preferential accumulation in lungs; it reduced cell viability and decreased 
downstream signaling and showed excellent efficacy in various xenograft cancer models, 
including pancreatic, colorectal, multiple myeloma, and breast cancer [39-42]. 
Importantly, ABI-009 has also shown efficacy in models of proliferative vasculopathy of 
the peripheral artery, supporting its use for indications related to the therapeutic 
remodeling of vascular disease [43].  
ABI-009 Preferential Uptake in Lungs compared to Oral Sirolimus in Rats  
We compared whole blood PK and tissue distribution at 24 hrs after ABI-009 IV 
administration (dose 1 mg/kg) in rats (N=5) to oral sirolimus[44] (dose 1.6 mg/kg) in rats 
(N=5), to determine relative uptake into the lung (target organ for PAH) and liver (major 
excretion route for sirolimus). Blood and tissue levels were measured by LC/MS/MS or 
HPLC (Figure 1). Blood levels at 24 hrs were comparable. The calculated tissue extraction 
ratios (conc of rapa in tissue/conc of rapa in blood) in the lung were 72 and 24 respectively 
for ABI-009 and oral sirolimus indicating a 3-fold higher lung targeting for ABI-009. In 
contrast, the extraction ratios for the liver were 27 and 43 respectively for ABI-009 and 




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= 0.01. The 500 μg dose of ABI-009 also significantly reduced medial fibrosis by 
qualitative analysis, P < 0.0001 t-test, and media cell proliferation by Ki-67 staining, P = 
0.02 t-test (Figure 2). 
The observation suggests that a single ABI-009 dose has an antiproliferative effect on 
vascular endothelial and smooth muscle cells and suggests that ABI-009 may also be 
active in the treatment of PAH that shares similar hyper-proliferation characteristics. 
 
Figure 2:  
Effect of ABI-009 on Injured Femoral Arteries 
 
(A) Representative femoral artery sections 28 days after injury and periadventitial injection of control or 
500 μg dose ABI-009. Both H&E and Masson’s trichrome staining demonstrate less luminal stenosis or 
medial fibrosis in the ABI-009-treated femoral arteries. ABI-009 500 μg dose reduced artery lumen 
stenosis (B) and medial fibrosis (C) 28 days after double-injury [43]. 
 
1.2.3.2. 
Translational Studies in Human Idiopathic PAH (IPAH) Tissues 
Goncharova et al. at University of Pittsburgh recently confirmed the importance of mTOR 
in human IPAH tissues. Immunohistochemical and immunoblot analyses revealed that 
mTOR signaling is markedly upregulated in small remodeled pulmonary arteries from 
human subjects with IPAH (Figure 3) [6]. Primary distal pulmonary artery vascular smooth 
muscle cells (PAVSMCs) from human subjects with IPAH have increased 
phosphorylation and activation of mTOR and its downstream effector S6 (S6) that is 
associated with increased proliferation and survival compared with normal controls 
(Figure 4) [6]. 
 
 
 


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Figure 3:  
mTOR Signalling is Activated in Small Pulmonary Arteries from Lungs 
of Patients with IPAH 
 
 
Dual immunohistochemical analysis of lung tissue specimens from 4 IPAH and 4 control (Contr) subjects 
with anti–P-S2481-mTOR, anti–P-S6 (red), and anti–smooth muscle actin (SMA) antibodies (green); DAPI 
staining (blue) was used to detect nuclei. A,B Images taken on a Nikon Eclipse 2000 microscope. Bar, 100 
μm. C, Statistical analysis of phosphorylated (P) proteins in SMA-positive areas in small pulmonary arteries 
from IPAH and control lungs. Data are in arbitrary units (AU); 4 human subjects per group. P indicates 
phosphorylated. *P<0.01 by unpaired Student t test. 
 
 






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Sirolimus given preventively (Days 1–21) or curatively (Days 21–42, Figure 7A) inhibited 
monocrotaline-induced PAH to a greater extent than did imatinib or fluoxetine as indicated 
by changes in pulmonary artery pressure, right ventricular hypertrophy and percentage 
of partially muscularized and fully muscularized vessels. Representative photographs of 
immunofluorescence staining for α-SMA in control rats and MCT 6-week rats treated with 
sirolimus, fluoxetine, imatinib, or vehicle from Day 21 to Day 42 showed a reversal of PAH 
as indicated by reduced arterial wall thickness of the pulmonary arteries (Figure 7B). The 
authors concluded that sirolimus was more effective in prevention and reversal of PAH in 
a rat monocrotaline model than imatinib or fluoxetine [9]. 
 
Figure 7: 
Inhibition of MCT-induced Pulmonary Hypertension by Sirolimus 
 
 
A. Pulmonary artery pressure (Pap), right ventricular hypertrophy index (RV/[LV +S] weights), and 
percentage of partially muscularized and fully muscularized vessels on Day 42 after saline (controls) or 
MCT administration combined with either sirolimus, fluoxetine, imatinib, or vehicle from Day 21 to Day 42 
(n = 10 in each group). *p < 0.05, **p< 0.01 compared with values in control rats. B. Representative 
photographs of immunofluorescence staining for α-SMA in control rats and MCT 6-week rats treated with 
sirolimus, fluoxetine, imatinib, or vehicle from Day 21 to Day 42. 
 
 
B 
 
 
 
DAPI 
 
 
α-SMA 
 
 


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In a study of sirolimus in a chronic hypoxia mouse model of PAH, sirolimus prevented 
hypoxia-induced increase of proliferative activity within the pulmonary vasculature, 
blocked hypoxia-triggered media thickening of intrapulmonary vessels, attenuated 
hypoxia-induced right ventricular hypertrophy, reduced hypoxia-triggered hypertrophy of 
individual cardiomyocytes, and reversed hypoxia-induced pulmonary vascular 
remodeling [7]. 
1.2.3.4. 
Pilot Clinical Study in PAH Patients Treated with Everolimus 
Seyfarth et al (2013) reported a pilot study with everolimus, an mTOR inhibitor, in 10 
patients suffering from PAH (n = 8) or chronic thromboembolic PH (n = 2) with progressive 
disease despite therapy with at least 2 vasodilating drugs [45].  All patients were treated 
with everolimus at a dose of 0.75 mg orally twice daily for 2 days in addition to their prior 
medication. The dose was adjusted thereafter to achieve a target serum level of 5-8 
ng/mL. The average daily dose was 2.1 mg (range 0.75-4.5 mg/day). Safety and 
tolerability were observed throughout the study. Pulmonary vascular resistance (PVR) 
and 6-minute walk distance (6MWD) were considered coprimary end points. In 2 patients, 
study medication was stopped prematurely because of an AE. One patient had acute 
bronchitis, and the other had right heart decompensation. The remaining 8 patients 
exhibited a significant 31% decrease in PVR (median [interquartile range], 1,012 [688–
1,344] vs. 663 [546–860] dyn s cm–5; P = 0.018) and an increase in 6MWD (median 
[interquartile range], 236 [139–350] vs. 298 [207–450] m; P = 0.069) after 6 months of 
treatment with everolimus. This pilot study suggests that mTOR inhibition may be a 
suitable approach for the treatment of PAH. 
1.2.3.5. 
Human Case Report in a PAH Patient Treated with Oral Sirolimus 
Wessler et al (2010) reported the case of a 61-year-old woman who presented with a 
large pancreatic mass and metastasis to the liver and biopsies consistent with an islet 
cell tumor [8]. In 2007, this patient was diagnosed with PAH with no response to nitric 
oxide treatment. Despite inhaled iloprost, she remained in New York Heart Association 
(NYHA) class 3. In 2009, she was treated with oral sirolimus (1 mg bid) in the setting of 
progressive disease to the liver. After 8 weeks her liver metastasis responded to 
treatment and the patient reported markedly decreased effort dyspnea. She was now able 
to exercise by climbing flights of stairs (NYHA class 2). The patient continued treatment 
with sirolimus for 10 months and by early 2010, she was NYHA class 1, her pulmonary 
artery systolic pressure by echocardiogram was normal and her EKG findings of right-
side heart strain had resolved. The authors concluded that the temporal association 
between sirolimus administration and the improvement in clinical, echocardiographic, and 
catheterization-documented pulmonary hypertension provides compelling evidence that 
sirolimus was effective in treating this patient’s PAH. It should be noted that there was no 
discussion of any AEs related to oral sirolimus and that as a cancer patient, the type of 
acceptable toxicities would be different than in a PAH patient. The toxicities of oral 
sirolimus (1 mg bid ie, 2 mg daily) are described in the Rapamune prescribing information 
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1.2.3.6. 
Clinical Studies with ABI-009 
In a phase 1 dose escalation, tolerability and pharmacokinetics study conducted at MD 
Anderson Cancer Center (Protocol CA-401), ABI-009 was well tolerated with evidence of 
responses and SD in various solid tumors including renal cell carcinoma and bladder 
cancer, both of which typically express mTOR [12]. Twenty-six patients were treated with 
45, 56.25, 100, 125, 150 mg/m2 ABI-009 per week for 3 weeks, followed by a week of rest 
(28-day cycle). ABI-009 administered intravenously. The maximum tolerated dose (MTD) 
was established at 100 mg/m2. 
Nineteen patients were evaluable for efficacy. One patient in the 45 mg/m2 (95 mg actual 
sirolimus dose) cohort diagnosed with adenocarcinoma of the kidney and with bone and 
intrathoracic metastases had a confirmed PR. The target lesion of this patient was 
reduced by 35.1% and the duration of response lasted 183 days. Two (11%) patients (at 
doses 45 and 125 mg/m2, with actual sirolimus doses of 88 mg and 193 mg, respectively) 
had an overall tumor evaluation of SD (confirmed): 1 patient with mesothelioma had SD 
for 365 days and 1 patient with a neuroendocrine tumor in the left axillary node had SD 
for 238 days.  
In the phase 1 study described above, for all cohorts and all grades, 25 of 26 (96%) 
patients experienced at least 1 AE. The most common AEs were mucosal inflammation 
(10 patients, 38%), fatigue (7 patients, 27%), rash (6 patients, 23%), diarrhea (6 patients, 
23%), and nausea (5 patients, 19%). Most of these AEs were grade 1/2 events, with only 
3 grade 3 nonhematologic AEs (2 elevated AST and 1 dyspnea). Specifically, at the 
maximum-tolerated dose (MTD, 100 mg/m2), all 7 patients experienced at least 1 AE of 
any grades, and the most common AEs were mucositis and fatigue (5 patients, 71% 
each). Four (15%) patients experienced at least 1 treatment-related SAE, including 
arrhythmia (grade 2) and mood alteration (grade 3) both in the 125 mg/m2 cohort, vomiting 
(grade 3) in the 45 mg/m2 cohort, and dyspnea (grade 3) in the 100 mg/m2 cohort. 
The most common hematologic AEs, for all cohorts and grades, were thrombocytopenia 
(58%), followed by hypokalemia (23%), anemia and hypophosphatemia (19% each), and 
neutropenia and hypertriglyceridemia (15% each). Most of these events were grade 1/2, 
and only 1 grade 4 hematologic event occurred (thrombocytopenia in the 150 mg/m2 arm). 
At the MTD, the only hematologic AE was a grade 3 anemia. 
For the present study in PAH patients, the starting dose will be 1 mg/m2, which is 100-
fold lower than the MTD obtained in the oncology phase 1 study. The original starting 
dose for this study was 10 mg/m2. Four patients were treated at this dose. Two patients 
developed dose-limiting grade 2 rash, associated with persistent intolerable pruritus. 
One of the 2 patients with rash developed cellulitis of the abdominal wall, most likely as 
a result of infection introduced through the skin by scratching. Another patient 
developed grade 1 paresthesia, which was also dose-limiting. As a result of these DLTs, 
the starting dose was amended to 1 mg/m2. 
 




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an approved sirolimus prodrug temsirolimus (day 5 sirolimus Cmax 133.9 ng/mL after 5 
days of IV daily administration of temsirolimus at 19.1 mg/m2 [51]), the Cmax with ABI-009 
was substantially higher. For continuous daily oral dosing of sirolimus at an average dose 
of 3.6 mg/day [47], the reported Cmax was 25.3 ng/mL. Compared to oral sirolimus, the 
predicted Cmax of ABI-009 at 1, 2.5, 5, and 7.5 mg/m2, the proposed doses to be testing 
in the planned PAH study, respectively were up to 6, folds higher – with the potential 
advantage to obtaining higher lung concentrations with ABI-009 along with potentially 
lower toxicities compared to oral sirolimus. 
1.2.3.8. 
Rationale for Starting Dose of ABI-009  
The starting dose of 1 mg/m2 for this study is selected based on the following 
considerations: 
• Clinical safety of ABI-009 has been previously evaluated in a phase 1 oncology 
study, with the MTD established at 100 mg/m2 of sirolimus (as nab-sirolimus or 
ABI-009) given weekly.  
• The original starting dose for this study was 10 mg/m2. Four patients were treated 
at this dose. Two patients developed dose-limiting grade 2 rash, associated with 
persistent intolerable pruritus. One of the 2 patients with rash developed cellulitis 
of the abdominal wall, most likely as a result of infection introduced through the 
skin by scratching. Another patient developed grade 1 paresthesia, which was also 
dose-limiting.  
• The revised starting dose for this study is 1 mg/m2 weekly, which is 10 folds lower 
than the initial starting dose. 
• Rapammune (oral sirolimus) dosing used chronically for transplant patients 
(Rapamune PI) is >8x higher than the proposed starting dose of ABI-009 [46]. 
Rapamune is dosed at 2-5 mg/day, which is 14-35 mg/week. Starting dose of ABI-
009 is 1 mg/m2/wk, which is about 1.7 mg/week assuming a BSA of 1.7 m2. 
• Safety of everolimus in the PAH patients (Seyfarth 2013) was studied in 10 patients 
that received an average of 2.1 mg/day or 14.7 mg/wk for 24 weeks in addition to 
standard PAH therapy [45]. Everolimus was well tolerated in that study. 
• Safety profiles of everolimus and Rapamune are similar. Everolimus dosing levels 
are similar to Rapamune dosing (Rapamune PI), with both being in the same range 
as the planned starting dose of ABI-009. 
• Drug-drug interaction potential of ABI-009 with standard PAH drugs is low (see 
Section 9.3). 
• Animal studies and clinical studies of ABI-009 have not shown any AEs that have 
not been previously described for mTOR inhibitors. 
 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
This phase 1/1b study will involve dose escalation to determine the MTD and safety of 16 
weeks of therapy (Dose-finding Safety Part) followed by up to 32 additional weeks of 
therapy (optional Extension Part) with ABI-009 IV in patients with PAH who are WHO 
Functional Class II or III despite best available background therapy. The MTD will be 
determined on the basis of the results from the safety evaluation.  
After the MTD is reached in phase 1, there will be up to 2 cohort expansions in phase 1b, 
one at the MTD and/or one alternate dose or schedule, to determine the recommended 
phase 2 dose (RP2D). The expanded cohorts will be such that up to 10 patients for each 
of the cohorts will be enrolled to obtain additional safety and efficacy data. The RP2D, 
which may differ from the MTD, will be determined on the basis of results from safety, 
efficacy, pharmacologic and correlative studies in this phase 1/1b study.  
The exploratory objective of the study is to evaluate pharmacokinetic information that may 
be correlated with safety and/or efficacy observations.  
2.2. 
Primary Endpoints 
• Dose finding phase: Establish the MTD, DLT, and safety of 16 weeks of ABI-009 
given IV 
• Safety profile of the up to 48 weeks of treatment 
2.3. 
Secondary Endpoints 
The following will be measured before treatment at baseline and at 17 weeks (after 16 
weeks of treatment in the Dose-finding Safety Part): 
• pulmonary vascular resistance (PVR) by right heart catheterization 
• pulmonary artery pressure (PAP) 
• pulmonary capillary wedge pressure (PCWP) 
• central venous pressure (CVP)  
The following will be measured at baseline, 5, 9, 13, and 17 weeks: 
• Doppler-echocardiographic assessments of right ventricular structure and function 
• 6-minute walk distance (6MWD)  
• WHO functional class  
• Pulmonary function test 


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The following will be measured every 8 weeks form the start of the Extension Part (ie, at 
week E9, E17, E25, and E33): 
• 6MWD  
• WHO Functional Class 
• Pulmonary function test 
 
2.4. 
Exploratory Endpoints 
• Pharmacokinetic (PK) profile and trough level of sirolimus for weekly treatment 
during the 16 weeks of Dose-finding Safety Part and every other week treatment 
during the Extension Part 
• Measurement of brain naturetic peptide (BNP), C-reactive protein (CRP) and 
troponin levels, indicative of right ventricular strain at baseline, 5, 9, 13, and 17 
weeks, and for BNP, every 8 weeks in the optional Extension Part (E9, E17, E25, 
E33) 
• Change from baseline at week 17, and to weeks E17 and E33 in the Extension 
Part in 36-Item Short Form Health Survey (SF-36) physical functioning scale 
• Change from baseline at week 17, and to weeks E17 and E33 in the Extension 
Part in emPHasis10 questionnaire 
 


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3. 
OVERALL STUDY DESIGN  
3.1. 
Study Design 
This study is a dose-finding prospective phase 1/1b, single arm, open-label, multi-
institutional study to determine the MTD, DLT, safety, and preliminary efficacy of 16 
weeks of IV ABI-009 treatment in patients with PAH who are WHO Functional Class II or 
III despite best available background therapy. 
The study will be conducted in compliance with International Conference on 
Harmonisation (ICH) Good Clinical Practices (GCPs). 
In phase 1, up to 24 patients will be enrolled using the standard 3+3 dose escalation 
design in the dose-finding phase. 
In phase 1b, an additional 4-7 patients in up to 2 expansion cohorts to obtain a total of  
up to10 patients at each of the 2 dose levels, MTD and/or an alternate dose or schedule. 
The MTD will be determined on the basis of the results from the safety evaluation. The 
RP2D, which may differ from the MTD, will be determined on the basis of results from 
safety, efficacy, and pharmacologic and correlative studies. 
Patients who, in the opinion of the investigator and Safety Committee, tolerate ABI-009 
well and achieve clinical benefit during the first 16-week Dose-finding Safety Part, and 
for whom there are no alternative therapies available, may opt to continue therapy 
(optional Extension Part) for up to an additional 32 weeks at their assigned dose or 
lower, if permanently reduced. The optional Extension Part should start within 4 weeks 
after the last dose of the 16-week Dose-finding Safety Part. 
Figure 9: 
Study Schema 
 


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3.2. 
Study Duration  
The study was originally expected to take approximately 30 months from first patient 
enrolled to last patient follow-up, including approximately 18 months of enrollment period, 
up to 16 weeks of treatment (Dose-finding Safety Part) (or until treatment is tolerated), 
followed by an optional Extension Part for up to 32 additional weeks of ABI-009, and at 
least a 28 days follow-up after the last dose either in the Dose-finding Safety or Extension 
Part, whichever is later. With the addition of the 7.5 mg/m2 dose cohort, it is anticipated 
that enrollment will take another 12 months for enrollment.   
3.3. 
End of Study, End of Treatment, End of Treatment Visit, Follow-up Period 
End of Study (EOS) is defined as either the date of the last visit of the last patient to 
complete the study, or the date of receipt of the last data point from the last patient that 
is required for primary, secondary, and/or exploratory analysis, as pre-specified in the 
protocol.  
End of Treatment (EOT) is defined as the date of the last dose of ABI-009. 
End of Treatment Visit is when safety and efficacy assessments and procedures are 
performed after the last treatment. For patients who complete the 16-week treatment, 
EOT visit occur at week 17 (±3 days).  For a patient who does not complete the 16-week 
treatment, EOT Visit must occur within 4 weeks (±7 days) after the last dose of ABI-009.   
Follow-up period is the on-study time period for at least 28 days after the last treatment 
either in the Dose-finding Safety Part or optional Extension Part, whichever is later. All 
patients that discontinue study drug and have not withdrawn full consent to participate in 
the study will continue in the follow-up phase for survival and therapy. Follow-up will 
continue up to 1 year approximately every 12 weeks (±3 weeks), or more frequently as 
needed, until withdrawal of consent, or the study closes, whichever is the earliest. This 
evaluation may be made by record review and/or telephone contact. 


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4. 
STUDY POPULATION 
4.1. 
Number of Patients 
In phase 1: Up to 24 patients will be enrolled using the standard 3+3 dose escalation 
design. 
In phase 1b: Additional 4-7 patients in up to 2 expansion cohorts to obtain a total of up to 
10 patients at each of the 2 dose levels, MTD and an alternate dose or schedule. 
4.2. 
Inclusion Criteria  
1) 
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) 
2) 
Must meet following hemodynamic definition prior to initiation of study drug 
a.  Mean PAP of ≥25 mmHg 
b. PCWP or left ventricular end diastolic pressure (LVEDP) of ≤15 mm 
c. PVR >5 mmHg/L/min (Woods unit) 
3) 
Functional class II or III according to the WHO set forth at the Dana Point 
Classification 2008 Meeting 
4) 
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    
5) 
Meet the following criteria determined by pulmonary function tests completed at 
screening: 
a. Forced expiratory volume in one second (FEV1) ≥55% of predicted normal   
b. FEV1: forced vital capacity (FVC) ratio ≥0.60 
6) 
6MWD ≥150 meters and ≤450 meters 
7) 
Male or non-pregnant and non-breast feeding female:  
• Females of child-bearing potential must agree to use effective contraception 
without interruption from 28 days prior to starting IP and while on study 
medication and have a negative serum pregnancy test (β-hCG) result at 
screening and agree to ongoing pregnancy testing during the course of the 
study, and after the end of study treatment. A second form of birth control is 
required even if she has had a tubal ligation.  
• Male patients must practice abstinence or agree to use a condom during sexual 
contact with a pregnant female or a female of childbearing potential while 
participating in the study. A second form of birth control is required even if he 
has undergone a successful vasectomy  
8) 
Ability to provide written informed consent by the patient or legal guardian 
 
4.3. 
Exclusion Criteria  
A patient will not be eligible for inclusion in this study if any of the following criteria apply: 


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1) 
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) 
2) 
History of malignancy in 2 years prior to enrollment 
3) 
Pulmonary hypertension (PH) belonging to groups 2 to 5 of the 2013 Nice 
classification 
4) 
Current or recent (<3 months) use of intravenous inotropic or vasopressor agents 
for the treatment of PAH 
5) 
Recent (<2 months) PAH-related hospital admission 
6) 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition including macrolide (eg, azithromycin, clarithromycin, dirithromycin, 
and erythromycin) and ketolide antibiotics 
7) 
Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy 
8) 
Uncontrolled hyperlipidemia (serum triglyceride ≥300 mg/dL) 
9) 
Serum cholesterol ≥350 mg/dL 
10) Surgery within 3 months of start date of study drug 
11) Baseline cytopenias: 
a.  Absolute Neutrophil Count ≤1.5 x 109/L 
b. Hemoglobin ≤9 g/dL 
c. Platelet count ≤100,000/mm3 
12) Baseline liver disease: ALT/AST, total bilirubin, alkaline phosphatase ≥1.5 x ULN 
13) Creatinine clearance (Cockroft formula) ≤30 mL/min  
14) Inability to attend scheduled clinic visits 
15) Prior use of an mTOR inhibitor within previous 6 months from enrollment 
16) Previous lung transplant 
17) Known Human Immunodefiiency Virus (HIV) 
18) Active Hepatitis B or Hepatitis C  
19) 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) 
20) Concomitant enrollment in another investigational treatment protocol for PAH  
21) 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 
 
 


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5. 
TABLE OF EVENTS 
The schedule of assessments in Table 2 outlines the specific time points for study 
assessments. 
 


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Table 2: 
Schedule of Assessments 
Visit Days 
Pre-
Treatment 
Study Treatment Monitoring During Up to 16 Weeks of Dose-finding Safety Part 
End of 
Treatment Visit l 
Optional Extension Part m 
Safety Follow-up n 
Weeks on  
Intervention 
Study Procedure a 
Baseline 
Screening b 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Week 
17 
Weekly, unless indicated 
28 days after last 
dose, then 
Q12W 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Vital Signs, height, and weight c 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
BSA d 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
E17, E33 
 
HIV and hepatitis tests 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Differential/Chemistry 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Every 2 weeks (E2-E32) 
 
NT Pro-BNP 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
E9, 17, 25, 33 
 
CRP 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
Troponin  
x  
 
 
 
 
x 
 
 
 
x 
 
 
 
x  
 
 
 
x 
 
 
Biomarker f 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Fasting Lipids 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
Every 4 weeks (E5-E29) 
 
Sirolimus level – central assays g 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sirolimus level – local assays g 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Every 2 weeks (E2-E32) 
 
Echocardiogram h 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
6-minute walk distance 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
E9, 17, 25, 33 
 
WHO Function Class 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
Pulmonary function test 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
Right heart catheterization i 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x i 
 
 
ABI-009 administration j 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
Concomitant meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse event assessment k 
Continuous, starting from signing of Informed Consent until 28 days after last dose of study drug 
SF-36 and emPHasis10 QNR  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
E17, E33 
 


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Protocol: PAH-001 
 
 
 
 
 
 
 
 
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Amendment 4: October 24, 2019 
 
a All visits are allowed to occur in a window of ±3 days unless otherwise specified. 
b Baseline screening visit will be done within 28 days prior to study treatment Day 1.  
c Height measurement is only required at screening. 
d BSA will be calculated at week 1 and recalculated if the weight changes by >10%. 
e Serum pregnancy test will be conducted at screening, urine pregnancy test will be conducted at week 17 or at the end of treatment visit. 
f Blood sample will be taken and stored for biomarker testing for patients who consent. 
g Sirolimus levels for central labs are done for patients in dose-finding phase of the study: week 1 predose, immediately after termination of infusion (end 
infusion), then 1, 2, and 4 hrs post infusion, and predose at weeks 2, 3, 4. Local labs for trough levels (predose) of sirolimus from week 2 and thereafter 
are done for all treated patients (in both Dose-finding Safety and Extension Part). An optional PK evaluation via local lab at weeks 1 and 3 (at 24, 48, 
and 72 hrs) are done for patients who consent in the Dose-finding Safety Part. 
h Echocardiogram studies will follow the Echo Core Lab Manual and will be uploaded to central lab for analysis.  
i RHC will be submitted to centralized core labs for analysis and is optional for patients who do not complete the 16-week treatment but opt to have RHC 
performed.  
j ABI-009 must be administered after all study specific assessments are done in a visit. 
k Continuous, starting from signing of Informed Consent until 28 days after last dose of study drug  
l End of Treatment Visit for patients who do not complete the 16-week treatment must be within 4 weeks of last study treatment (±7 days).  
m Optional Extension Part is for patients who tolerated ABI-009 well and showed clinical benefit during the Dose-finding Safety Part based on the opinion 
of the investigator and Safety Committee. This Extension Part should start within 4 weeks after the last dose of ABI-009 in the Dose-finding Safety Part. 
ABI-009 will be given at the originally assigned dose (or lower if reduced) for a maximum of 32 additional weeks, followed by an evaluation on week 33 
for select assessments: urine pregnancy test, NT Pro-BNP, 6MWD, WHO functional class assessment, pulmonary function test, and SF-36 and 
emPHasis10 questionnaires. If treatment discontinues prior to week 32, the week 33 assessments should be done within 4 weeks of last treatment. 
n Safety follow-up will continue for a minimum of 28 days then approximately every 12 weeks (±3 weeks) by phone call after the last treatment either in 
the Dose-finding Safety Part or optional Extension Part. Follow-up will continue up to 1 year approximately every 12 weeks (±3 weeks), or more 
frequently as needed, until withdrawal of consent, or the study closes, whichever is the earliest. 
 


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6. 
PROCEDURES 
6.1. 
Screening Evaluations 
This study will be conducted at approximately 5 sites in the US. Additional sites may be 
added. 
Each patient who enters into the screening period for the study receives a unique patient 
identification number before any study-related procedures are performed. The patient 
identification number will be assigned. This number will be used to identify the patient 
throughout the clinical study and must be used on all study documentation related to that 
patient.  
The patient identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a patient is rescreened.  
Before patients may be entered into the study, the Sponsor requires a copy of the site’s 
written IRB/IEC approval of the protocol, informed consent form, and all other patient 
information and/or recruitment material, if applicable. A signed and dated Institutional 
Review Board (IRB) approved informed consent form (latest approved version) must be 
obtained from each patient prior to performing any study-specific procedures. All patients 
or legally acceptable representatives must personally sign and date the consent form 
before commencement of study-specific procedures. Patients who lack capacity to 
understand protocol requirements will be excluded. Adverse Events are to be collected 
for a patient upon signing the informed consent until 28 days after last dose of study drug.  
Screening evaluations will be performed for all patients to determine study eligibility.  
These evaluations must be completed within 28 days prior to enrollment. Any questions 
regarding patient eligibility should be directed to Aadi or other sponsor-nominated 
representatives or designees for approval. 
The following procedures are to be completed during the screening period, after signed 
informed consent has been obtained, designated in the Schedule of Assessments, 
Table 2. The 6MWD test will be conducted following guidelines by American Thoracic 
Society [52]. 
• Informed consent 
• Medical history, demographics 
• Complete blood count with differential and chemistry panel 
• Physical exams, vital signs, height, and weight  
• Serum pregnancy test 
• NT Pro-BNP 
• CRP 
• Troponin 


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• Biomarker test (optional) 
• Fasting lipid test 
• SF-36 and emPHasis10 questionnaire 
• Echocardiogram  
• 6MWD test 
• WHO Functional Class 
• Pulmonary function test 
• Right heart catheterization  
• Concomitant medication 
• HIV test  
• Hepatitis B surface antigen, hepatitis B and C antibody tests 
• Adverse Events 
A patient is considered eligible when the investigator decides that the patient has met all 
eligibility criteria. The investigator is to document this decision and date, in the patient’s 
medical record and in/on the electronic case report form (eCRF). 
All screening tests and procedures must be performed within 28 days of study day 1. 
Once eligibility is confirmed, a site representative will complete and fax a patient eligibility 
criteria worksheet to an Aadi representative. The Aadi representative will acknowledge 
receipt of the paperwork and confirm enrollment for that individual patient.  
6.2. 
Dose-finding Safety Part (up to 16 weeks) 
A patient is considered enrolled on study day 1 when the IP, ABI-009, is first administered. 
ABI-009 is to be administered after all other protocol-specified pre-dose assessments 
have been performed during each visit that it is required. ABI-009 will be administered 
weekly for 16 weeks. All weekly visits are allowed to occur in a window of ±3 days. 
6.2.1. 
Every Week Assessments During the 16-week Dose-finding Safety Part 
The following assessments will be performed every week: 
• Physical exams, vital signs and weight  
• Complete blood count with differential and chemistry panel 
• Sirolimus PK  
• Concomitant medications  
• Adverse Events 
Week 1 evaluations may be omitted if screening evaluations are performed within 72 
hours. For complete analyte listing, refer to Table 3. 


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Table 3: 
Analyte Listing 
Chemistry 
Hematology 
Other Labs 
Sodium 
WBC 
Pregnancy test 
Potassium 
RBC 
Sirolimus PK  
Bicarbonate 
Hemoglobin 
HIV 
Chloride 
Hematocrit 
HBV sAg 
Total protein 
MCV 
HBV cAb 
Albumin 
MCH 
HCV Ab 
Calcium 
MCHC 
Total Cholesterol  
Magnesium 
RDW 
HDL 
Phosphorus 
Platelets 
LDL 
Glucose 
Differential: 
Triglyceride 
BUN 
-Neutrophils 
Biomarker 
development  
Creatinine 
-Lymphocytes 
NT Pro-BNP 
Total bilirubin 
-Monocytes 
CRP 
Alkaline phosphatase -Eosinophils 
Troponin 
AST (SGOT) 
-Basophils 
 
ALT (SGPT) 
 
 
Amylase 
 
 
Lipase 
 
 
 
6.2.2. 
Every 4-Week Assessments During the 16-week Dose-finding Safety 
Part 
The following assessments will be performed every 4 weeks at week 5, week 9, and week 
13: 
• NT Pro-BNP 
• CRP 
• Troponin 
• Fasting lipids 
• Echocardiogram 
• 6MWD test 
• WHO Functional Class 
• Pulmonary function test 


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All efficacy measurements will occur prior to the administration of ABI-009 during the visit.   
6.2.3. 
Efficacy Assessment During the 16-week Dose-finding Safety Part 
Efficacy assessment will occur at baseline and at EOT Visit (to evaluate the utility 
(potential for clinical efficacy) of ABI-009 in the treatment of PAH as measured by a 
change in PVR and other hemodynamic parameters. Change from baseline in 6MWD 
(absolute difference in distance), echo cardiographic assessments and WHO functional 
class will be measured. Changes from baseline to week 17 in 36-Item Short Form Health 
Survey (SF-36) physical functioning scale and in emPHasis10 questionnaire will be 
measured as exploratory endpoints. 
For efficacy assessment, all sites need to refer to standard instructions provided, 
including Right Heart Catherization (RHC), RHC Parameter Worksheet, Six Minute 
Walking Test (6MWT) Instruction, Borg dyspnea index (BDI), WHO Classification 
Worksheet, Echocardiogram Instruction, and Pulmonary Function Test Instruction. 
Echocardiogram and RHC assessments will be submitted to centralized core labs for 
analysis. 
6.3. 
End of Treatment Visit Assessment 
End of Treatment Visit assessment for a patient is when efficacy and safety assessments 
and procedures are performed after the last treatment in the 16-week Dose-finding Safety 
Part. For patients who complete the 16-week treatment, EOT assessments occur on week 
17 (±3 days) and for patients who do not complete the 16-week treatment, EOT 
assessments must occur within 4 weeks (±7 days) after the last dose of ABI-009.  
• Physical exams, vital signs, and weight  
• Complete blood count with differential and chemistry panel 
• Concomitant medications  
• Adverse Events 
• Urine pregnancy  
• NT Pro-BNP 
• CRP 
• Troponin 
• Biomarker analysis (optional) 
• Fasting lipids 
• Echocardiogram 
• 6MWD test 
• WHO Functional Class 
• Pulmonary function test 
• Right heart catheterization 


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• SF-36 and emPHasis10 questionnaire 
For patients who fail to complete the 16-week treatment, RHC can be performed if 
patients opt to have the procedure. RHC results from these patients will be analyzed 
separately from those of patients who complete the 16-week treatment. 
6.4. 
Pharmacokinetic Study  
A PK study of sirolimus will be performed with limited PK sampling on all patients in the 
dose-finding portion of the study during the first 4 weeks of treatment, assessed via 
central lab: 
• Blood samples will be obtained on day 1 (week 1) and will be taken immediately 
predose (before infusion), immediately after termination of infusion (end infusion), 
then at 1 hr, 2 hrs, and 4 hrs post infusion. Thereafter, blood samples will be taken 
every week immediately predose for the next 3 weeks (weeks 2, 3, and 4) to 
determine a trough level.  
Additional PK samples for sirolimus analysis will be obtained for local lab assessment to 
help correlate AEs with blood levels during treatment: 
• From all treated patient in the 16-week Dose finding Safety Part (including 
expansion cohort/s): Immediately predose starting at week 2 and continuing for the 
duration of the study 
• From all treated patients in the up to 32 weeks of Extension Part: Immediately 
predose starting at week E2 and continuing every other week for the duration of 
the study 
• Optional PK samples for consenting patients: During weeks 1 and 3 of the Dose-
finding Safety Part at 24, 48, and 72 hours post infusion. 
Note that T = 0 is defined as the start of infusion, ie, all sample collection times are relative 
to the start of infusion. The sample at the end of the infusion is collected immediately after 
the infusion is stopped. If the duration of infusion is changed, the sample should be 
collected immediately before termination of the infusion and the time noted.  
Whole-blood samples will be collected in EDTA tubes for determination of sirolimus in a 
central laboratory. 
Sample Handling for Central Lab: 
• Collect approximately 4 mL blood into vacutainer tubes containing EDTA as the 
anticoagulant. 
• Mix the whole blood gently but thoroughly in the tube immediately after collection. 
• Split the sample into two tubes. One tube will be kept as a back-up sample. 
• Ensure that both tubes are labeled identically. 
• Store the blood samples deep frozen at a temperature between -20 and -80°C. 
• The samples will be shipped to a designated laboratory. 
Sample Labeling: 
The following information should be on each sample: 


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• Protocol number 
• Patient ID 
• Nominal sample time point 
• Collection clock time and date 
A simple regression model will be applied to assess the relationship of the 
pharmacokinetic parameters with dose. 
6.5. 
Samples for Optional Biomarker Analysis During the 16-week Dose-
finding Safety Part 
For consented patients enrolled in the expansion cohort, blood samples will be collected 
for blood outgrowth endothelial cell (BOECs) at baseline and EOT to correlate response 
to therapeutic intervention with ABI-009.  
6.6. 
Assessments During the Optional Extension Part 
For patients who tolerated ABI-009 well and showed clinical benefit during the Dose-
finding Safety Part, based on the investigator and Safety Committee’s judgement can 
continue treatment for up to an additional 32 weeks. All assessments must be done prior 
to dosing: 
Every visit when ABI-009 is given (E1 through E32):  
• 
Physical exams 
• 
Vital signs and weight  
• 
Concomitant medications 
Every 2 visits when ABI-009 is given from E2 through E32: 
• 
Complete blood count with differential and chemistry panel 
SirolimusEvery 4 weeks when ABI-009 is given (E5 through E29): 
• 
Lipids 
Every 8 weeks (ie, at weeks E9, E17, E25, and E33): 
• 
6MWD test 
• 
WHO Functional Class 
• 
Pulmonary function test 
• 
NT Pro-BNP 
Every 16 weeks (ie, at weeks E17 and E33): 
• 
SF-36 and emPHasis10 questionnaire 
 


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Protocol: PAH-001 
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7.
DESCRIPTION OF STUDY TREATMENTS
7.1. 
ABI-009 Dosage, Administration, and Schedule 
The planned treatment period is 16 weeks, with ABI-009 given weekly. Patients, who 
based on the investigator and Safety Committee’s assessment, tolerate ABI-009 and 
show clinical benefit during the 16-week Dose-finding Safety Part, and for whom there 
are no alternative therapies available, may opt to continue therapy in the optional 
Extension Part, with ABI-009 given weekly at the originally assigned dose (or lower, if 
permanently reduced) for up to 32 additional weeks. A physician must be available at the 
time of administration of IP on dosing days that correspond to study visits. Supportive 
care per the institution’s normal standard of care including concomitant medications can 
be provided at the investigator’s discretion. 
In the dose-finding portion of the study, 4 dose levels of ABI-009 will be tested in 
cohorts of 3 patients each (1, 2.5, 5, and 7.5 mg/m2, see Table 1 and below), using the 
3+3 dose escalation de-escalation design. There will be no intra-patient dose escalation 
allowed.  Escalation to the next dose level with a new cohort of 3 patients will occur 
after no DLT was observed in the first treatment cycle of 4 weeks. If a DLT occurs in a 
cohort, additional 3 patients will be recruited to the cohort. If no further DLTs occur, then 
a new cohort of 3 patients at the next higher dose level can be enrolled. If 2/6 patients 
at dose level 1a experience a DLT, then that cohort will be closed to further enrollment 
and the study may be terminated. If 2/6 patients at dose levels 2a, 3a, or 4a experience 
a DLT, then the previous dose level is considered the MTD.  
It is estimated that a maximum of up to 24 patients will be required to achieve the MTD; 
however, MTD could be reached with as few as 9 patients. Patients will be allowed to 
dose reduce by one dose level for reasons of toxicity, with a maximum of 2 dose 
reductions allowed for a patient. At the lowest dose level, a dose reduction of 25% will be 
allowed. 
Dose Level 
1a 
2a 
3a 
4a 
ABI-009 Weekly Dose (mg/m2) 
1 
2.5 
5 
7.5 
Note: The original protocol included dose levels 1 (10 mg/m2), 2, (20 mg/m2) and 
3 (30 mg/m2), and dose level -1 (5 mg/m2). 
7.2. 
Dose Modification and Stopping Rules 
7.2.1. 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
If treatment cannot be administered on the planned visit date, ABI-009 may be 
administered ±3 days from the scheduled date. Prior to ABI-009 administration, patients 
must meet the following hematological requirements: 
•
ANC ≥1.5 x 109/L
•
Platelet count ≥100 x 109/L


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• Hemoglobin ≥9 g/dL 
The treatment will be on hold up to 14 days until the patient has fulfilled these criteria. 
In the event of clinically significant AE in any part of the study, treatment may be withheld, 
and supportive therapy administered as clinically indicated. If the toxicity or event is not 
grade 3/4 and resolves to baseline or grade 1 in less than or equal to 14 days of stopping 
therapy, then treatment may be restarted.  
A DLT is defined as a study-drug -related grade ≥3 hematologic AE or persistent 
intolerable nonhematologic AE of any grade that requires dose reduction or permanent 
discontinuation of the study-drug, in the opinion of the investigator. 
Dose reduction of ABI-009 to the next lower dose level should be considered as clinically 
indicated for patients who are receiving ABI-009 at above the lowest dose level. At the 
lowest dose level, a dose reduction of 25% will be allowed. Once a dose has been 
reduced, it must not be increased to the previous level. A maximum of 2 dose reductions 
are allowed for a patient in the entire duration of the study. 
The maximum delay between a missed scheduled dose and the next one (whichever 
dose was missed) should not be longer than 14 days. Approval from the Medical Monitor 
is required to restart study treatment after ≥21 days of interruption.  


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8. 
STUDY DRUG MANAGEMENT  
8.1. 
Description of ABI-009  
8.1.1. 
ABI-009 Packaging, Labeling, and Storage 
ABI-009 will be supplied by the Sponsor in single-use vials as lyophilized product. Each 
single-use 50-mL vial will contain 100 mg sirolimus and human albumin as a stabilizer. 
Each vial will be labeled according to country-specific regulatory requirements for labeling 
of IPs.  
Unopened vials of ABI-009 should be stored in a refrigerator (2°-8°C; 36°-46°F) in original 
cartons to protect from light. Reconstituted ABI-009 may be stored for up to 4 hours at 2-
8°C (36°- 46°F), followed by 4 hours at room temperature (<25°C) in the IV bag. Both 
unopened vials of ABI-009 and reconstituted ABI-009 should be stored in an area free of 
environmental extremes and must be accessible only to study personnel. 
Temperature records for ABI-009 must be made available to Aadi or Sponsor nominated 
Contract Research Organization monitoring teams for verification of proper study drug 
storage. 
8.2. 
ABI-009 Accountability, Disposal, and Compliance 
Only completely unused study drug vials should be retained by the site until a 
representative from Aadi or Sponsor-nominated CRO has completed an inventory. 
Partially used and completely used vials should be destroyed according to the site’s 
guidelines, and their disposition should be recorded on the Investigational Drug 
Accountability Record Form. 
The Investigator, or designee, shall record the dispensing of study drug to patients and 
any remaining study drug after dosing in a study drug accountability record. The study 
drug record will be made available to Aadi or authorized Aadi-designated monitoring 
personnel for the purpose of accounting for the study drug supply. Inspections of the study 
drug supply for inventory purposes and assurance of proper storage will be conducted as 
necessary. Any significant discrepancy will be recorded and reported to Aadi or their 
designee and a plan for resolution will be documented. 
Accurate recording of all ABI-009 administration will be made in the appropriate section 
of the patient’s eCRF and source documents. The investigator or designee is responsible 
for accounting for all study-specific IP either administered or in their custody during the 
course of the study. 
8.3. 
ABI-009 Reconstitution 
NOTE: It is not a requirement to use filter needles in the preparation, or in-line filters 
during the administration of ABI-009. In any event, filters of pore size less than 15 microns 
(15 µm) must not be used. 
ABI-009 will be reconstituted by appropriate study personnel following the Pharmacy 
Manual, and administered to the patient in the study site. The Investigator will calculate 
the BSA of the patient in order to determine the total amount of ABI-009 to be 
administered. 


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8.4. 
Receipt and Return of ABI-009 
Upon receipt of the study drug supplies, the Investigator or designee will conduct an 
inventory and sign both copies of the study drug receipt and forward one copy to the 
address indicated on the form. One copy of the receipt and the packing slip must be 
retained in the Investigator’s regulatory file records. 
A representative from Aadi or his/her designee will inspect the study drug inventory, Drug 
Accountability Record form(s), and will arrange for the disposition of any remaining 
unused study drug. No study drug may be returned to Aadi without the representative 
from Aadi or other Aadi-designated personnel first inspecting the study drug inventory 
and accountability documentation. 
 


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9. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
All concomitant treatments, including blood and blood products, must be reported on the 
eCRF. Throughout the study, investigators may prescribe any concomitant medications 
or treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 9.2. 
Concomitant therapies are to be collected from enrollment/randomization through the 
EOT Visit. Therapy name including indication, dose, frequency, route, start date and stop 
date will be recorded on each patient’s eCRF(s). 
9.1. 
Permitted Medications and Procedures 
The investigator must be informed as soon as possible about any medication taken from 
the time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF. The minimum requirement is that drug name, dose, and the dates 
of administration are to be recorded. Additionally, a complete list of all prior cancer 
therapies will be recorded in the eCRF. 
Patients should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheas, and 
analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines. WBC growth factors may be administered at the discretion of the 
investigator, consistent with institutional guidelines. 
Extreme precaution must be taken with contraceptives (either combined or progesterone 
only), as it is not known if there is the potential of inhibition/induction of enzymes that 
affect the metabolism of estrogens and/or progestins.  
9.2. 
Prohibited Medications and Procedures 
The use of certain medications, and illicit drugs within 5 half-lives or 28 days, whichever 
is shorter prior to the first dose of study drug and for the duration of the study will not be 
allowed. If a prohibited medication is required for single use (such as for a procedure) 
while study drug is held, the Aadi medical monitor can approve such use. 
The following medications or non-drug therapies are prohibited: 
• Other anti-cancer therapy while on treatment in this study. 
• Antiretroviral drugs (patients with known HIV are ineligible for study participation). 
• Herbal remedies (eg, St. John’s wort) unless approval is granted by the medical 
monitor. 
• Sirolimus is metabolized primarily by CYP3A4. Drugs that are strong inhibitors or 
inducers of CYP3A4 may only be used under special circumstances (eg, as a 
single use for a procedure) while treatment with study drug is interrupted. The list 
may be modified based on emerging data.  
• Use of any known CYP3A4 substrates with narrow therapeutic window (such as 
fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, 


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terfanide) within the 14 days prior to receiving the first dose of ABI-009.  Other 
medications may be allowed if there is agreement between the sponsor and 
investigator 
• Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to 
receiving the first dose of ABI-009  
9.3. 
Drug-Drug Interactions of ABI-009 and Standard PAH Medications 
The potential for drug-drug interactions between ABI-009 and standard PAH medications 
is low. Sirolimus is a substrate for (i.e., it is metabolized by) both cytochrome P-450 3A4 
(CYP3A4) and p-glycoprotein (P-gp). It is not an inducer or inhibitor of CYP3A4 or P-gp. 
Several of the standard PAH medications, eg, bosentan, sildenafil, ambrisentan, 
treprostinil etc are also metabolized primarily by CYP3A4. Since none of these 
medications are strong inducers or inhibitors of CYP3A4, they are used in together in 
combination for treatment of PAH. Therefore, addition of ABI-009 to standard PAH 
therapy is not expected to alter the PK of these drugs or cause adverse drug interactions. 
Nevertheless, in the planned clinical study the starting dose is 10X below the MTD 
determined in an oncology phase 1 study, giving a very wide safety margin for the 
patients. Additionally, safety will be closely monitored along with the PK of sirolimus in 
the PAH phase 1 study, and it may be possible to identify if any AE is related to drug 
interactions through analysis of sirolimus plasma levels.   
 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Study Endpoints 
Primary Endpoints:  
MTD, DLTs, and toxicities and safety profile of 16 weeks, as well as safety profile of the 
up to 48 weeks of ABI-009 given IV, in patients with PAH who are WHO Functional Class 
II or III despite best available background therapy. 
In the dose-finding portion of the study, 4 dose levels of ABI-009 will be tested in cohorts 
of 3 patients each (1, 2.5, 5, and 7.5 mg/m2), using the 3+3 dose escalation design. There 
will be no intra-patient dose escalation allowed. Escalation to the next dose level with a 
new cohort of 3 patients will occur after no DLT was observed in the first treatment cycle 
of 4 weeks. If a DLT occurs in a cohort, additional 3 patients will be recruited to the cohort. 
If no further DLTs occur, then a new cohort of 3 patients at the next higher dose level can 
be enrolled. If 2/6 patients at dose level 1a experience a DLT, then that cohort will be 
closed to further enrollment and the study may be terminated. If 2/6 patients at dose levels 
2a or 3a experience a DLT, then the previous dose level is considered the MTD.  
The treated population will be the analysis population for all safety analyses. Adverse 
events will be coded using the Medical Dictionary for Medical Activities (MedDRA) and 
grouped by their system organ class and preferred term. Summary tables will include the 
number and percentage of treatment-emergent and treatment-related AEs, AEs of special 
interest, SAEs, and incidence of patients experiencing dose modifications, dose 
delay/dose not given, dose interruptions, and/or premature discontinuation of IP due to 
an AE.  
An external Safety Monitoring Committee (SMC) will assess safety data periodically as 
needed.  
Secondary Endpoint(s):  
The following will be measurements will be summarized at baseline and at 17 weeks (after 
16 weeks of treatment in the Dose-finding Safety Part): 
• pulmonary vascular resistance (PVR) by right heart catheterization 
• pulmonary artery pressure (PAP) 
• pulmonary capillary wedge pressure (PCWP) 
• central venous pressure (CVP)  
The following will be measurements will be summarized at baseline, 5, 9, 13, and 17 
weeks: 
• Doppler-echocardiographic assessments of right ventricular structure and function 
• 6-minute walk distance (6MWD)  
• WHO functional class  
• Pulmonary function test 


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The following will be measurements will be summarized every 8 weeks of the Extension 
Part (ie, at week E9, E17, E25, and E33): 
•
6MWD
•
WHO Functional Class
•
Pulmonary function test
Exploratory Endpoint(s): 
•
Pharmacokinetic (PK) profile and trough level of sirolimus for weekly treatment
during the 16 weeks of Dose-finding Safety Part and every other week treatment
during the Extension Part
•
Measurement of brain naturetic peptide (BNP), C-reactive protein (CRP) and
troponin levels, indicative of right ventricular strain at baseline, 5, 9, 13, and 17
weeks and for BNP, every 8 weeks in the optional Extension Part (E9, E17, E25,
E33)
•
Change from baseline to week 17 and to weeks E17 and E33 in the Extension Part
in 36-Item Short Form Health Survey (SF-36) physical functioning scale
•
Change from baseline to week 17 and to weeks E17 and E33 in the Extension Part
in emPHasis10 questionnaire
10.2. 
Sample Size Considerations 
The dose-escalation portion of this clinical study will enroll up to 24 patients. Dose 
escalation will follow the 3+3 rule to establish the MTD. Three planned dose levels are to 
be used (Table 1). The minimum number of patients required to establish the MTD is 9 
patients. In case there is a dose limiting toxicity at each of the 4 dose levels, each cohort 
of 3 patients will be expanded to 6 patients, in which case a total of 24 patients will be 
treated.   
After the MTD is achieved, up to 2 cohorts (one including the MTD and one alternate dose 
or schedule) will be expanded to enroll a total of up to 10 patients in each cohort to further 
evaluate safety and preliminary utility (potential for clinical efficacy) of ABI-009 in the 
treatment of PAH.  
10.3. 
Pharmacokinetic Analysis 
Pharmacokinetic analysis will include all patients in the phase 1 dose escalation who 
received ABI-009 during the first 4 weeks (central analysis).  
An additional (local) PK study will be conducted to obtain trough sirolimus levels 
throughout the study (both in the first 16-week Dose-finding Safety (weekly samples) and 
optional 32-week Extension Part (every-2-week samples) from all enrolled patients , as 
well as a more detailed sirolimus PK from weeks 1 and 3 from patients who consent. The 
whole blood concentration of sirolimus will be summarized by descriptive statistics as 
appropriate. A simple regression model will be applied to assess the relationship of the 
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11. 
MONITORING, RECORDING AND REPORTING OF ADVERSE 
EVENTS  
11.1. 
Toxicities of ABI-009 
ABI-009 is a formulation of sirolimus. No unexpected toxicities not already known for 
sirolimus (Rapamune®) or the sirolimus prodrug, temsirolimus (Torisel®), were identified 
in the nonclinical toxicity studies, or observed in the phase 1 studies for ABI-009. 
More details on the known precautions, warnings, and AEs of sirolimus and rapalogs are 
found in the Rapamune® and Torisel® Package Inserts [46, 53]. 
An AE is any noxious, unintended, or untoward medical occurrence that may appear or 
worsen in a patient during the course of a study. It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the patient’s 
health, including laboratory test values (as specified by the criteria below), regardless of 
etiology. Any worsening (ie, any clinically significant adverse change in the frequency or 
intensity of a preexisting condition) should be considered an AE. A diagnosis or syndrome 
should be recorded on the AE page of the eCRF rather than the individual signs or 
symptoms of the diagnosis or syndrome.  
Abuse, withdrawal, sensitivity or toxicity to the IP should be reported as an AE. Overdose, 
accidental or intentional, whether or not it is associated with an AE should be reported on 
the overdose CRF. Any sequela of an accidental or intentional overdose of the IP should 
be reported as an AE on the AE CRF. If the sequela of an overdose is an SAE, then the 
sequela must be reported on an SAE report form and on the AE CRF. The overdose 
resulting in the SAE should be identified as the cause of the event on the SAE report form 
and CRF but should not be reported as an SAE itself.  
All patients will be monitored for AEs during the study. Assessments may include 
monitoring of any or all of the following parameters: the patient’s clinical symptoms, 
laboratory, pathological, radiological or surgical findings, physical examination findings, 
or other appropriate tests and procedures. 
All AEs will be recorded by the investigator from the time the patient signs informed 
consent until 28 days after the last dose of ABI-009 and those SAEs made known to the 
investigator at any time thereafter that are suspected of being related to IP. AEs and SAEs 
will be recorded on the AE page of the eCRF and in the patient’s source documents. All 
SAEs must be reported to Aadi Drug Safety within 24 hours of the investigator’s 
knowledge of the event by facsimile, or other appropriate method, using the SAE Report 
Form, or approved equivalent form. 
The investigator’s clinical judgment is used to determine whether a patient is to be 
removed from treatment due to an AE. The investigator is responsible for ensuring that 
all AEs observed by the investigator or reported by the patient that occur after the first 
dose of IP through the EOT Visit are reported using the applicable eCRF (eg, AE 
Summary CRF).  
11.2. 
Evaluation of Adverse Events  
The investigator must assign the following AE attributes: 


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• AE diagnosis or syndrome(s), if known (if not known, signs or symptoms) 
• Dates of onset and resolution (if resolved) 
• Severity [and/or toxicity per protocol] 
• Assessment of relatedness to the IP 
• Assessment of relatedness to protocol-required procedures  
• Action taken 
The AE toxicity grading scale used will be the NCI CTCAE Version 4.03.   
11.3. 
Serious Adverse Events 
11.3.1. 
Definition of Serious Adverse Events 
An SAE is defined as an AE that meets at least 1 of the following serious criteria: 
• fatal 
• life-threatening (places the patient at immediate risk of death) 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• other medically important serious event 
An AE would meet the criterion of “requires hospitalization”, if the event necessitated an 
in-patient admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any of 
the serious criteria, the event could be classified as an SAE under the criterion of “other 
medically important serious event”.  Examples of such events could include allergic 
bronchospasm, convulsions, blood dyscrasias, drug-induced liver injury, or events that 
necessitate an emergency room visit, outpatient surgery, or urgent intervention. 
Since the criteria for the CTCAE grading scale differs from the regulatory criteria for SAEs, 
if AEs correspond to grade 4 “life threatening” CTCAE grading scale criteria 
(eg, laboratory abnormality reported as grade 4 without manifestation of life threatening 
status), it will be left to the investigator’s judgment to also report these abnormalities as 
SAEs. For any AE that applies to this situation, comprehensive documentation of the 
event’s severity status must be recorded in the patient’s medical record.   
11.3.2. 
Reporting Procedures for Serious Adverse Events 
Any AE that meets any criterion for an SAE requires the completion of an SAE Report 
Form in addition to being recorded on the AE page/screen of the eCRF.  All SAEs must 
be reported to Aadi Drug Safety within 24 hours of the investigator’s knowledge of the 
event by facsimile, or other appropriate method, using the SAE Report Form, or approved 
equivalent form. This instruction pertains to initial SAE reports as well as any follow-up 
reports. 


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The investigator is required to ensure that the data on these forms is accurate and 
consistent. This requirement applies to all SAEs (regardless of relationship to IP) that 
occur during the study (from the time of signing of the informed consent form to 28 days 
after the last dose of IP), and those made known to the investigator at any time thereafter 
that are suspected of being related to IP.   
The SAE report should provide a detailed description of the SAE and include a concise 
summary of hospital records and other relevant documents. If a patient died and an 
autopsy has been performed, copies of the autopsy report and death certificate are to be 
sent to Aadi Drug Safety as soon as these become available. Any follow-up data will be 
detailed in a subsequent SAE Report Form, or approved equivalent form, and sent to 
Aadi Drug Safety.  
Where required by local legislation, the investigator is responsible for informing the 
IRB/EC of the SAE and providing them with all relevant initial and follow-up information 
about the event. The investigator must keep copies of all SAE information on file including 
correspondence with Aadi and the IRB/EC. 
11.4. 
Pregnancy and Breast Feeding Reporting 
If a pregnancy occurs in a female patient, or female partner of a male patient, while the 
patient is taking protocol-required therapies report the pregnancy to Aadi as specified 
below. In addition to reporting any pregnancies occurring during the study, investigators 
should monitor for pregnancies that occur up to 3 months after the last dose of protocol-
required therapies.  
The investigator will follow the female patient until completion of the pregnancy, and must 
notify Aadi Drug Safety immediately about the outcome of the pregnancy (either normal 
or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved 
equivalent form. If a lactation case occurs while the female patient is taking protocol-
required therapies, report the lactation case to Aadi as specified below. In addition to 
reporting a lactation case during the study, investigators should monitor for lactation 
cases that occur up to 1 week after the last dose of protocol-required therapies. 
 


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12. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
12.1. 
Discontinuation from Investigational Product 
The following events are considered sufficient reasons for discontinuing a patient from 
the IP: 
• 
AE(s) (that are intolerable) 
• 
Physician decision 
• 
Withdrawal of consent (from treatment only) 
• 
Death 
• 
Lost to follow up 
• 
Protocol violation 
• 
Other (to be specified on the eCRF) 
The reason for treatment discontinuation should be recorded in the eCRF and in the 
source documents. 
12.2. 
Discontinuation from the Study 
The following events are considered sufficient reasons for discontinuing a patient from 
the study: 
• 
Withdrawal of consent 
• 
Death 
• 
Lost to follow up 
• 
Protocol violation 
• 
Other (to be specified on the eCRF) 
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents. 
At the time of withdrawal, it should be determined whether the patient is withdrawing from 
treatment alone, or from treatment and collection of further data (eg, survival). Every effort 
should be made to collect survival data after patient withdraws from treatment.  
Patients have the right to withdraw from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or at the institution. 
12.3. 
Investigator or Sponsor Decision to Withdraw or Terminate Patient’s 
Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a patient(s) from IP and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time prior 
to study completion.    
Patients may be eligible for continued treatment with Aadi IP and/or other 
protocol-required therapies by a separate protocol or as provided for by the local country’s 
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13. 
REGULATORY OBLIGATIONS 
13.1. 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site. Updates to the template are to 
be communicated formally in writing from Aadi to the investigator. The written informed 
consent document is to be prepared in the language(s) of the potential patient population. 
Before a patient’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the patient after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or the IP is administered.  
The investigator is also responsible for asking the patient if the patient has a primary care 
physician and if the patient agrees to have his/her primary care physician informed of the 
patient’s participation in the clinical study. If the patient agrees to such notification, the 
investigator is to inform the patient’s primary care physician of the patient’s participation 
in the clinical study. If the patient does not have a primary care physician and the 
investigator will be acting in that capacity, the investigator is to document such in the 
patient’s medical record. 
The acquisition of informed consent and the patient’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the patient’s medical 
records, and the informed consent form to be signed and personally dated by the patient 
or a legally acceptable representative and by the person who conducted the informed 
consent discussion. The original signed informed consent form is to be retained in 
accordance with institutional policy, and a copy of the signed consent form is to be 
provided to the patient or legally acceptable representative. 
If a potential patient is illiterate or visually impaired and does not have a legally acceptable 
representative, the investigator must provide an impartial witness to read the informed 
consent form to the patient and must allow for questions. Thereafter, both the patient and 
the witness must sign the informed consent form to attest that informed consent was 
freely given and understood.   
13.2. 
Institutional Review Board/Independent Ethics Committee  
A copy of the protocol, proposed informed consent form, other written patient information, 
and any proposed advertising material must be submitted to the IRB for written approval. 
A copy of the written approval of the protocol and informed consent form must be received 
by Aadi before recruitment of patients into the study and shipment of Aadi IP. 
The investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
investigator is to notify the IRB of deviations from the protocol or SAEs occurring at the 
site and other AE reports received from Aadi, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB approval [IRBs only]/renewal 
[IRBs and IECs] throughout the duration of the study. Copies of the investigator’s reports 
and the IRB continuance of approval must be sent to Aadi. 


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13.3. 
Patient Confidentiality 
The investigator must ensure that the patient’s confidentiality is maintained for documents 
submitted to Aadi. 
• Patients are to be identified by a unique patient identification number. 
• Where permitted, date of birth is to be documented and formatted in 
accordance with local laws and regulations. 
• On the CRF demographics page, in addition to the unique patient identification 
number, include the age at time of enrollment. 
• For SAEs reported to Aadi, patients are to be identified by their unique patient 
identification number, initials (for faxed reports, in accordance with local laws 
and regulations), and date of birth (in accordance with local laws and 
regulations). 
• Documents that are not submitted to Aadi (eg, signed informed consent forms) 
are to be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB direct access to review the patient’s original medical 
records for verification of study-related procedures and data. Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are 
important to the evaluation of the study. The investigator is obligated to inform and obtain 
the consent of the patient to permit such individuals to have access to his/her study-
related records, including personal information. 
13.4. 
Protocol Amendments   
If Aadi amends the protocol, agreement from the investigator must be obtained. The IRB 
must be informed of all amendments and give approval. The investigator must send a 
copy of the approval letter from the IRB to Aadi. 
13.5. 
Termination of the Study 
Aadi reserves the right to terminate the study at any time. Both Aadi and the investigator 
reserve the right to terminate the Investigator’s participation in the study according to the 
study contract. The investigator is to notify the IRB in writing of the study’s completion or 
early termination and send a copy of the notification to Aadi. 
 


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14.
DATA HANDLING AND RECORDKEEPING
14.1. 
Data/Documents
The investigator must ensure that the records and documents pertaining to the conduct 
of the study and the distribution of the investigational product are complete, accurate, 
filed, and retained. Examples of source documents include: hospital records; clinic and 
office charts; laboratory notes; memoranda; checklists; dispensing records; recorded data 
from automated instruments; copies or transcriptions certified after verification as being 
accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy; 
and the laboratories, as well as copies of eCRFs or CD-ROM. 
14.2. 
Data Management 
Data will be collected via eCRF and entered into the clinical database. These data will be 
electronically verified through use of programmed edit checks specified by the clinical 
team.  Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary. Resolutions to these issues will be reflected 
in the database.  An audit trail within the system will track all changes made to the data. 
14.3. 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including patients not receiving protocol-required therapies) as 
stipulated in the protocol for each patient in the study. For patients who withdraw prior to 
completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 2), the investigator can search publicly available 
records (where permitted) to ascertain survival status.  
This ensures that the data set(s) produced as an outcome of the study is/are as 
comprehensive as possible.  
14.4. Sample Storage and Destruction 
Any blood, biomarker or pharmacokinetic sample collected according to the Schedule of 
Assessments (Table 2) can be analyzed for any of the tests outlined in the protocol and 
for any tests necessary to minimize risks to study patients. This includes testing to ensure 
analytical methods produce reliable and valid data throughout the course of the study. 
This can also include, but is not limited to, investigation of unexpected results, incurred 
sample reanalysis, and analyses for method transfer and comparability.  
If informed consent is provided by the patient, Aadi can do additional testing on remaining 
samples (ie, residual and back-up) to investigate and better understand the disease, the 
dose response and/or prediction of response to ABI-009, and characterize aspects of the 
molecule (eg, mechanism of action/target, metabolites). Results from this analysis are to 
be documented and maintained, but are not necessarily reported as part of this study. 
Samples can be retained for up to 20 years.  
Since the evaluations are not expected to benefit the patient directly or to alter the 
treatment course, the results of biomarker, biomarker development, or other exploratory 
studies are not placed in the patient’s medical record and are not to be made available to 


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the patient, members of the family, the personal physician, or other third parties, except 
as specified in the informed consent.  
The patient retains the right to request that the sample material be destroyed by 
contacting the Investigator. Following the request from the patient, the investigator is to 
provide the sponsor with the required study and patient number so that any remaining 
blood or tumor samples and any other components from the cells can be located and 
destroyed. Samples will be destroyed once all protocol-defined procedures are completed.  
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the request 
of the patient through the Investigator, at the end of the storage period, or as appropriate 
(eg, the scientific rationale for experimentation with a certain sample type no longer 
justifies keeping the sample). If a commercial product is developed from this research 
project, the sponsor owns the commercial product. The patient has no commercial rights 
to such product and has no commercial rights to the data. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1. 
Study Monitoring 
The Aadi representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that patient confidentiality is respected. 
The Aadi representative is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research. Monitoring will include on-site visits with the investigator and his/her staff as 
well as any appropriate communications by mail, email, fax, or telephone.  During 
monitoring visits, the facilities, IP storage area, eCRFs, patient’s source documents, and 
all other study documentation will be inspected/reviewed by the Aadi representative in 
accordance with the Study Monitoring Plan.   
The investigator agrees to cooperate with the clinical monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing eCRFs, 
are resolved. 
15.2. 
Audits and Inspections 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Aadi’s Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, and laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, ICH 
GCP, and applicable regulatory requirements. 
 


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16. 
PUBLICATIONS 
The results of this study may be published in a medical publication, journal, or may be 
used for teaching purposes.  Additionally, this study and its results may be submitted for 
inclusion in all appropriate health authority study registries, as well as publication on 
health authority study registry websites, as required by local health authority regulations. 
Selection of first authorship will be based on several considerations, including, but not 
limited to study participation, contribution to the protocol development, and analysis and 
input into the manuscript, related abstracts, and presentations in a study. 


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17. 
REFERENCES 
1. 
Waxman AB, and Zamanian RT (2013). Pulmonary arterial hypertension: new 
insights into the optimal role of current and emerging prostacyclin therapies. Am J 
Cardiol  111, 1A-16A. 
2. 
Rich S (2009). The effects of vasodilators in pulmonary hypertension: pulmonary 
vascular or peripheral vascular? Circulation. Heart failure  2, 145-150. 
3. 
Macchia A, Marchioli R, Tognoni G, Scarano M, Marfisi R, Tavazzi L, and Rich S 
(2010). Systematic review of trials using vasodilators in pulmonary arterial 
hypertension: why a new approach is needed. Am Heart J  159, 245-257. 
4. 
Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galie N, Gomez-Sanchez 
MA, Grimminger F, Grunig E, Hassoun PM, et al. (2013). Imatinib mesylate as add-
on therapy for pulmonary arterial hypertension: Results of the randomized 
IMPRES study. Circulation  127, 1128-1138. 
5. 
Krymskaya VP, Snow J, Cesarone G, Khavin I, Goncharov DA, Lim PN, Veasey 
SC, Ihida-Stansbury K, Jones PL, and Goncharova EA (2011). mTOR is required 
for pulmonary arterial vascular smooth muscle cell proliferation under chronic 
hypoxia. FASEB J  25, 1922-1933. 
6. 
Goncharov DA, Kudryashova TV, Ziai H, Ihida-Stansbury K, Delisser H, 
Krymskaya VP, Tuder RM, Kawut SM, and Goncharova EA (2014). Mammalian 
Target of Rapamycin Complex 2 (mTORC2) Coordinates Pulmonary Artery 
Smooth Muscle Cell Metabolism, Proliferation, and Survival in Pulmonary Arterial 
Hypertension. Circulation  129, 864-874. 
7. 
Paddenberg R, Stieger P, von Lilien AL, Faulhammer P, Goldenberg A, Tillmanns 
HH, Kummer W, and Braun-Dullaeus RC (2007). Rapamycin attenuates hypoxia-
induced pulmonary vascular remodeling and right ventricular hypertrophy in mice. 
Respir Res  8, 15. 
8. 
Wessler JD, Steingart RM, Schwartz GK, Harvey BG, and Schaffer W (2010). 
Dramatic improvement in pulmonary hypertension with rapamycin. Chest  138, 
991-993. 
9. 
Houssaini A, Abid S, Mouraret N, Wan F, Rideau D, Saker M, Marcos E, Tissot 
CM, Dubois-Rande JL, Amsellem V, et al. (2013). Rapamycin reverses pulmonary 
artery smooth muscle cell proliferation in pulmonary hypertension. Am J Respir 
Cell Mol Biol  48, 568-577. 
10. 
Cool CD, Groshong SD, Oakey J, and Voelkel NF (2005). Pulmonary 
hypertension: cellular and molecular mechanisms. Chest  128, 565S-571S. 
11. 
Wiederrecht GJ, Sabers CJ, Brunn GJ, Martin MM, Dumont FJ, and Abraham RT 
(1995). Mechanism of action of rapamycin: new insights into the regulation of G1-
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