Clinical trial NCT02494570
Conditions: Malignant PEComa
Keywords: malignant PEComa, perivascular epithelioid cell tumors
Sponsor: Aadi Bioscience, Inc.
Start date: 2015-10-01; Completion date: 2022-04-01
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A phase 2 multi-center investigation of efficacy of nab-sirolimus (formerly known as ABI-009 or nab-rapamycin) in patients with advanced malignant perivascular epithelioid cell tumor (PEComa).

Detailed description:
This was a phase 2, single-arm, open-label, multi-center study to determine the efficacy and safety profile of nab-sirolimus in patients with advanced malignant PEComa. Patients were required to have measurable disease at baseline (per RECIST v1.1). Eligible patients received nab-sirolimus at 100 mg/m2 by IV infusion (over 30 minutes) weekly for 2 weeks followed by a week of rest (ie, on Day 1 and Day 8 in 21-day cycles). Patients remained on treatment until they experienced progressive disease or unacceptable toxicity, withdrew consent, or physician's decision. Patients who discontinued treatment entered the on-study Follow-up period for survival.

Computed tomography or magnetic resonance imaging (MRI) scans were performed at screening, every 6 weeks for the first year, then every 12 weeks thereafter until the end of treatment. Throughout treatment with nab-sirolimus, patients were routinely assessed for toxicities, the need for dose modifications, and response assessments.

The sample size was targeted to be \~30 patients in order to provide a reasonably precise estimate of the true ORR. Assuming an observed ORR of 30% and a sample size of 30, the lower bound of the 95% confidence interval (CI) for the estimated ORR would exclude values less than 14.7%.

The primary analysis was predefined to be conducted when all patients have had the opportunity to be treated for at least 6 months. The study remained open for 3 additional years and the final analysis occured at study closure.

Arms: arm 1: Patients with malignant PEComa received nab-sirolimus on Days 1 and 8 of every 21-day cycle, as a 30-minute IV infusion.
Interventions: intervention 1: nab-Sirolimus
Intervention descriptions: intervention 1: Patients received nab-sirolimus at 100 mg/m2 on Days 1 and 8 of a 21-day cycle by intravenous infusion over 30 minutes.

Protocol documents:
Prot_SAP_000.pdf: 
nab-Sirolimus (ABI-009)
Protocol: PEC-001 and Statistical Analysis Plan
Confidential and Proprietary 
Cover Page
Protocol including Statistical Analysis Plan 
Last Approved Version & Date: Amendment 2, 11-Dec-2015
Protocol Title: 
A phase 2 multi-center investigation of efficacy of 
ABI-009 
(nab-rapamycin) 
in 
patients 
with 
advanced malignant perivascular epithelioid cell tumors 
(PEComa) 


ABI-009  
Protocol: PEC-001 
 
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Confidential and Proprietary 
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ITLE PAGE 
 
A phase 2 multi-center investigation of efficacy of ABI-009 (nab-
rapamycin) in patients with advanced malignant perivascular 
epithelioid cell tumors (PEComa) 
 
 
INVESTIGATIONAL PRODUCT (IP): 
 
ABI-009 
PROTOCOL NUMBER: 
 
PEC-001 
Version History: 
 
 
Date Final: 
 
June 16, 2015 
Amendment 1 
 
Aug 9, 2015 
Amendment 2 
 
Dec 11, 2015 
IND NUMBER: 
 
125,669   
SPONSOR NAME/ ADDRESS: 
 
 
 
AADi, LLC 
16730 Calle De Catalina 
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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PROTOCOL SYNOPSIS 
 
Study Title 
A phase 2 multi-center investigation of efficacy of ABI-009 (nab-rapamycin) in patients 
with advanced malignant perivascular epithelioid cell tumor (PEComa) 
 
Study Number: PEC-001 
 
Study Phase: 2 
 
Name of Investigational Product (IP) 
ABI-009, rapamycin protein-bound nanoparticles for injectable suspension (albumin 
bound), nab-rapamycin, nanoparticle albumin-bound rapamycin 
 
Indication 
Patients with advanced (metastatic or locally advanced) malignant PEComa, who have 
not been previously treated with an mTOR inhibitor. 
 
Objectives 
Primary Objective  
The primary objective of this study is to investigate the efficacy of the mTOR inhibitor 
ABI-009 in advanced malignant PEComa.  
Secondary Objectives  
The secondary objectives are to further investigate the efficacy and safety of 
intravenous (IV) ABI-009 100 mg/m2 given weekly for 2 of 3 weeks in patients with 
advanced malignant PEComa.  
Exploratory Objectives  
• To evaluate investigator assessed ORR 
• To evaluate pharmacokinetic/pharmacodynamic relationships for safety and/or 
efficacy endpoints  
• To evaluate tumor biomarkers 
 


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Endpoints 
Primary Endpoint  
The primary endpoint is objective overall response rate (ORR), as determined by 
independent radiologic assessment using Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. 
Secondary endpoints 
The secondary endpoints are duration of response (DOR), progression-free survival 
(PFS) rate at 6 months, PFS, overall survival (OS), safety/tolerability. 
• DOR, PFS at 6 months, median PFS, and median OS will be assessed 
separately in subgroups of patients with metastatic disease and locally advanced 
disease.  
• Safety will be analyzed in all treated patients. 
Exploratory Endpoints 
• Investigator assessed ORR 
• Pharmacokinetic/pharmacodynamic relationships for safety and/or efficacy 
endpoints  
• To evaluate tumor biomarkers: 
o Blood samples will be obtained for cell-free plasma DNA collection 
(pretreatment, Cycle 4/Day 1, and post-treatment) for all patients.  
 Molecular analysis of cell-free plasma DNA assay using next-generation 
sequencing to assess the prevalence of mutations identified in the primary 
tumor sample over time as a measure of response to therapy.  
o Tumor biopsy mutation analysis to assess resistance mechanisms. Pre-
treatment tumors (archival or fresh tissue biopsies) are required for all 
patients on this study to confirm diagnosis. This sample will also be used for 
baseline mutational analysis. In addition, an optional tumor biopsy will be 
collected for patients who provide additional consent at the end of treatment 
and/or if a patient experiences progression while on study. 
 
Study Design 
This study is a prospective phase 2, single arm, open-label, multi-institutional study to 
determine the efficacy and safety profile of ABI-009 administered by IV infusion in 
patients with advanced malignant PEComa.  
The study will be conducted in compliance with International Conference on 
Harmonisation (ICH) Good Clinical Practices (GCPs). 


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Sample Size 
At least 30 evaluable patients will be enrolled.  
Study Population 
Malignant PEComa histology may be assessed locally in each institution for enrollment 
but will be retrospectively confirmed by a centralized review for every patient after 
enrollment to meet prespecified criteria for malignant PEComa. If a patient does not 
meet retrospectively these criteria, a replacement will be considered. 
Patient Eligibility 
Inclusion Criteria 
A patient will be eligible for inclusion in this study only if all of the following criteria are 
met: 
1. Patients must have a histologically confirmed diagnosis of malignant PEComa 
that is either metastatic or locally advanced and for which surgery is not a 
recommended option. 
2. Patients must have available tumor block along with the corresponding pathology 
report (or approximately 30 unstained slides, with a minimum of 16 slides), 
and/or fresh biopsy to allow retrospective centralized confirmation of malignant 
PEComa and for mTOR pathway analysis and biomarker analysis.  
3. Patients must have one or more measurable target lesions by CT scan or MRI. 
Measurable disease by RECIST v1.1.  
4. Patients must not have been previously treated with an mTOR inhibitor. 
5. Prior treatment (investigational or other), chemotherapy, radiotherapy, surgery, or 
other therapeutic agents (except mTOR inhibitors) is allowed, if completed after 5 
half-lives or ≥28 days prior to enrollment, whichever is shorter. 
6. Eligible patients, 18 years or older, with Eastern Cooperative Oncology Group 
(ECOG) performance status 0 or 1. 
7. Patients must have the following blood chemistry levels at screening (obtained 
≤14 days prior to enrollment (local laboratory): 
a. total bilirubin ≤1.5 x upper limit of normal (ULN) mg/dl 
b. AST ≤2.5 x ULN (≤5 x ULN if attributable to liver metastases) 
c. serum creatinine ≤1.5 x ULN 
8. Adequate biological parameters as demonstrated by the following blood counts 
at screening (obtained ≤14 days prior to enrollment, local laboratory): 
a. Absolute neutrophil count (ANC) ≥1.5 × 109/L; 
b. Platelet count ≥100,000/mm3 (100 × 109/L); 
c. Hemoglobin ≥9 g/dL.  
9. Serum triglyceride <300 mg/dL; serum cholesterol < 350 mg/dL. 


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10.  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. 
11.  Life expectancy of >3 months, as determined by the investigator. 
12.  Ability to understand and sign informed consent. 
13.  Willingness and ability to comply with scheduled visits, laboratory tests, and 
other study procedures. 
Exclusion Criteria 
A patient will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. Patients with lymphangioleiomyomatosis (LAM) are excluded.  
2. Known active uncontrolled or symptomatic central nervous system (CNS) 
metastases. A patient with controlled and asymptomatic CNS metastases may 
participate in this study. As such, the patient must have completed any prior 
treatment for CNS metastases ≥28 days (including radiotherapy and/or surgery) 
prior to start of treatment in this study and should not be receiving chronic 
corticosteroid therapy for the CNS metastases. 
3. Active gastrointestinal bleeding. 
4. Pre-existing thyroid abnormality is allowed provided thyroid function can be 
controlled with medication. 
5. Uncontrolled serious medical or psychiatric illness. Patients with a “currently 
active” second malignancy other than non-melanoma skin cancers, carcinoma in 
situ of the cervix, resected incidental prostate cancer (staged pT2 with Gleason 
Score ≤ 6 and postoperative PSA <0.5 ng/mL), or other adequately treated 
carcinoma-in-situ are ineligible. Patients are not considered to have a “currently 
active” malignancy if they have completed therapy and are free of disease for ≥1 
year). 
6. Liver-directed therapy within 2 months of enrollment. Prior treatment with 
radiotherapy (including radio-labeled spheres and/or cyberknife, hepatic arterial 
embolization (with or without chemotherapy) or cyrotherapy/ablation) is allowed if 
these therapies did not affect the areas of measurable disease being used for 
this protocol. 


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7. Recent infection requiring systemic anti-infective treatment that was completed 
≤14 days prior to enrollment (with the exception of uncomplicated urinary tract 
infection or upper respiratory tract infection). 
8. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate 
therapy. 
9. Unstable coronary artery disease or myocardial infarction during preceding 6 
months. 
10. Receiving any concomitant antitumor therapy. 
11. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary 
hypertension. 
12. 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.  
13. Known Human Immunodeficiency Virus (HIV). 
14. Active Hepatitis B or Hepatitis C. 
 
Length of Study 
The study is expected to take approximately 32 months from first patient enrolled to last 
patient follow-up, including approximately 24 months of enrollment period, an estimated 
6 months of treatment (or until treatment is no longer tolerated) and an end of treatment 
visit at 4 weeks (+/- 7 days) after last treatment.   
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 (EOT) for a patient is defined as the date of the last dose of ABI-009. 
End of Treatment Visit for a patient is when safety assessments and procedures are 
performed after the last treatment, which must occur at least 4 weeks (± 7 days) after 
the last dose of ABI-009.   
Follow-up period is the on-study time period after the EOT Visit. 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 initiation anticancer therapy. Follow 
up will continue approximately every 12 weeks (+/- 3 weeks), until death, 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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Study Treatments 
Patients will receive ABI-009 100 mg/m2 for 2 of every 3 weeks by IV infusion over 30 
minutes. Two dose reduction levels will be allowed: 75 mg/m2 and 56 mg/m2. Patients 
will continue to therapy until disease progression, unacceptable toxicity, until in the 
opinion of the investigator the patient is no longer benefiting from therapy, or at the 
patients discretion. 
Overview of Key Efficacy Assessments 
Patients will be evaluated for complete response (CR), partial response (PR), stable 
disease (SD), or progressive disease (PD) by CT imaging. Contrast enhanced MRI can 
also be used, as long as the same modality is used throughout the study. Baseline scan 
results can be accepted from outside institutions, but must be done within 4 weeks of 
starting therapy and must include (as clinically indicated), chest abdominal, and pelvic 
CT or MRI. The first response assessment by CT or MRI scans documenting target 
lesions will be done 6 weeks after first treatment and should be repeated every 6 weeks 
for the first year, then every 12 weeks thereafter until disease progression. If an initial 
observation of objective response (CR or PR) is made, a confirmation scan should be 
done at 6 weeks after initial observation. Scans should continue on schedule regardless 
of delays in ABI-009 dosing. The primary endpoint, ORR, will be determined by 
independent radiologist(s). The independent radiologic review will follow a separate 
imaging charter. 
After disease progression, patients will be followed for survival every 12 weeks, or more 
frequently as needed, until death, withdrawal of consent, or the study closes, whichever 
is the earliest.  
Overview of Key Safety Assessments 
Safety and tolerability will be monitored through continuous reporting of treatment-
emergent and treatment-related adverse events (AEs), AEs of special interest, 
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 until 28 days after the last dose of IP. Adverse events will be graded 
by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. 
Physical examination, vital sign, laboratory assessments (eg, serum chemistry, 
hematology), and ECOG performance status will be monitored. All SAEs (regardless of 
relationship to IP) will be followed until resolution. Laboratory analysis will be performed 
as per study schedule. 
Statistical Considerations 
Efficacy Analyses: 
The primary analysis will address all study objectives and it will be conducted when all 
patients have had the opportunity to be treated for at least 6 months. All primary, 
secondary, and exploratory efficacy and safety analyses will be conducted at the time 


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of the primary analysis, with the exception of the biomarkers which may be analyzed at 
a later date.    
The primary endpoint is ORR by independent radiologic review, and is defined as the 
proportion of patients who achieve a confirmed PR or CR per RECIST 1.1.  
The focus of the study is to estimate the ORR in patients treated with ABI-009. The 
number and percentage of patients achieving response will be summarized and an 
exact 95% confidence interval (CI) will be provided. Assuming an observed ORR of 
30%, the lower bound of the 95% CI for the estimated ORR will exclude values less 
than 14.7%. With 30 patients the half-width of the 95% CI for the estimated ORR will be 
no more than 18.7%.  
Analysis of secondary efficacy endpoints DOR, PFS rate at 6 months, PFS, and OS will 
be done separately for 2 subgroups of patients: 1) those with metastatic disease; and 2) 
those with locally advanced disease for which surgery is not a recommended option. 
Some of the patients in the locally advanced subgroup may be clinically indicated to 
receive surgery if there is sufficient tumor shrinkage, which would introduce a bias to the 
analysis.  
For patients with metastatic disease, DOR, PFS at 6 months, median PFS, and OS will 
be summarized using Kaplan-Meier (KM) analysis. Quartiles with 95% CIs will be 
summarized. The number of patients with locally advanced disease for which surgery is 
not an option is expected to be small; therefore DOR, PFS at 6 months, median PFS, 
and OS for these patients will be summarized by descriptive statistics. 
Safety Analyses: 
The treated population (Full Analysis Set) 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 AEs, serious 
AEs, fatal AEs and other AEs of interest. Safety will be analyzed in both patient groups 
together (metastatic and locally advanced). 
An external Data Monitoring Committee (DMC) will assess safety data approximately 
when a third of patients enrolled and received at least 2 cycles of therapy. For a full 
description of statistical analysis methods please refer to Section 10. 


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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................... 1 
PROTOCOL SYNOPSIS ................................................................................................. 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................... 17 
1. 
INTRODUCTION .......................................................................................... 21 
1.1. 
Malignant PEComa Disease Background .................................................... 21 
1.2. 
ABI-009 Background .................................................................................... 23 
1.2.1. 
Rapamycin and Rapalogs ............................................................................ 23 
1.2.2. 
ABI-009 (nab-Rapamycin) ............................................................................ 24 
1.2.2.1. 
Preclinical Studies with ABI-009 ................................................................... 25 
1.2.2.2. 
Clinical Studies with ABI-009 ....................................................................... 26 
1.2.2.3. 
ABI-009 (nab-Rapamycin) Pharmacokinetics (PK) ...................................... 28 
1.3. 
Rationale for the Study ................................................................................. 29 
1.3.1. 
Rationale for the Use of ABI-009 in Advanced Malignant PEComas ........... 29 
1.3.2. 
Rationale for the Schedule of Administration of ABI-009 ............................. 30 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................... 32 
2.1. 
Objectives .................................................................................................... 32 
2.1.1. 
Primary Objectives ....................................................................................... 32 
2.1.2. 
Secondary Objectives .................................................................................. 32 
2.1.3. 
Exploratory Objectives ................................................................................. 32 
2.2. 
Endpoints ..................................................................................................... 32 
2.2.1. 
Primary Endpoint .......................................................................................... 32 
2.2.2. 
Secondary Endpoints ................................................................................... 32 
2.2.3. 
Exploratory Endpoints .................................................................................. 32 
3. 
OVERALL STUDY DESIGN ......................................................................... 34 
3.1. 
Study Design ................................................................................................ 34 
3.2. 
Study Duration ............................................................................................. 34 
3.3. 
End of Study, End of Treatment, End of Treatment Visit, Follow-up 
Period ........................................................................................................... 34 
4. 
STUDY POPULATION ................................................................................. 36 
4.1. 
Number of Patients ...................................................................................... 36 
4.2. 
Inclusion Criteria .......................................................................................... 36 


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4.3. 
Exclusion Criteria ......................................................................................... 37 
5. 
TABLE OF EVENTS .................................................................................... 39 
6. 
PROCEDURES ............................................................................................ 43 
6.1. 
Screening Evaluations ................................................................................. 43 
6.2. 
Treatment Period ......................................................................................... 44 
6.2.1. 
Day 1 Assessment ....................................................................................... 44 
6.2.2. 
Day 8 Assessment ....................................................................................... 45 
6.2.3. 
Response Assessment ................................................................................ 45 
6.3. 
End of Treatment Visit Assessment ............................................................. 47 
6.4. 
Follow-up Period for Survival and Initiation of Anticancer Therapy .............. 48 
6.5. 
Pharmacokinetic Study ................................................................................ 48 
6.6. 
Biomarker Development ............................................................................... 48 
7. 
DESCRIPTION OF STUDY TREATMENTS ................................................ 50 
7.1. 
ABI-009 Dosage, Administration, and Schedule .......................................... 50 
7.2. 
Dose Modification and Stopping Rules ........................................................ 50 
7.2.1. 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation .......................................................................... 50 
7.2.2. 
Hepatotoxicity Stopping Rules ..................................................................... 53 
7.2.2.1. 
Criteria for Permanent Discontinuation of ABI-009 Due to Potential 
Hepatotoxicity............................................................................................... 54 
7.2.2.2. 
Criteria for Conditional Withholding of ABI-009 Due to Potential 
Hepatotoxicity............................................................................................... 54 
7.2.2.3. 
Criteria for Rechallenge with ABI-009 After Potential Hepatotoxicity ........... 55 
7.2.3. 
Overdose ..................................................................................................... 55 
8. 
STUDY DRUG MANAGEMENT ................................................................... 56 
8.1. 
Description of ABI-009 ................................................................................. 56 
8.1.1. 
ABI-009 Packaging, Labeling, and Storage ................................................. 56 
8.2. 
ABI-009 Accountability, Disposal, and Compliance...................................... 56 
8.3. 
ABI-009 Reconstitution ................................................................................ 56 
8.4. 
Receipt and Return of ABI-009 .................................................................... 58 
9. 
CONCOMITANT MEDICATIONS AND PROCEDURES .............................. 59 
9.1. 
Permitted Medications and Procedures ....................................................... 59 
9.2. 
Prohibited Medications and Procedures ....................................................... 59 


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10. 
STATISTICAL CONSIDERATIONS ............................................................. 61 
10.1. 
Study Endpoints, Analysis Sets, and Covariates .......................................... 61 
10.1.1. 
Study Endpoints ........................................................................................... 61 
10.1.2. 
Analysis Sets ............................................................................................... 61 
10.1.3. 
Covariates and Subgroups ........................................................................... 62 
10.2. 
Sample Size Considerations ........................................................................ 62 
10.3. 
Data Monitoring Committee (DMC) .............................................................. 62 
10.4. 
Primary Analysis .......................................................................................... 63 
10.5. 
Planned Methods of Analysis ....................................................................... 63 
10.5.1. 
General Considerations ............................................................................... 63 
10.5.2. 
Primary Efficacy Endpoint ............................................................................ 63 
10.5.3. 
Secondary Efficacy Endpoints ...................................................................... 64 
10.5.4. 
Safety Endpoints .......................................................................................... 64 
10.6. 
Pharmacokinetic Analysis ............................................................................ 65 
11. 
MONITORING, RECORDING AND REPORTING OF ADVERSE 
EVENTS ....................................................................................................... 66 
11.1. 
Toxicities of ABI-009 .................................................................................... 66 
11.2. 
Evaluation of Adverse Events ...................................................................... 67 
11.3. 
Serious Adverse Events ............................................................................... 67 
11.3.1. 
Definition of Serious Adverse Events ........................................................... 67 
11.3.2. 
Reporting Procedures for Serious Adverse Events ...................................... 68 
11.4. 
Pregnancy and Breast Feeding Reporting ................................................... 68 
12. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY ........ 69 
12.1. 
Discontinuation from Investigational Product ............................................... 69 
12.2. 
Discontinuation from the Study .................................................................... 69 
12.3. 
Investigator or Sponsor Decision to Withdraw or Terminate Patient’s 
Participation Prior to Study Completion ........................................................ 70 
13. 
REGULATORY OBLIGATIONS ................................................................... 71 
13.1. 
Informed Consent ......................................................................................... 71 
13.2. 
Institutional Review Board/Independent Ethics Committee .......................... 71 
13.3. 
Patient Confidentiality .................................................................................. 72 
13.4. 
Protocol Amendments .................................................................................. 72 
13.5. 
Termination of the Study .............................................................................. 72 


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14. 
DATA HANDLING AND RECORDKEEPING .................................................. 73 
14.1. 
Data/Documents .......................................................................................... 73 
14.2. 
Data Management ........................................................................................ 73 
14.3. 
Investigator Responsibilities for Data Collection .......................................... 73 
14.4. 
Sample Storage and Destruction ................................................................. 73 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................... 75 
15.1. 
Study Monitoring .......................................................................................... 75 
15.2. 
Audits and Inspections ................................................................................. 75 
16. 
PUBLICATIONS ........................................................................................... 76 
17. 
REFERENCES ............................................................................................. 77 
 
 
 


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LIST OF TABLES 
Table 1:  Treatment-related Grade 1–4 Hematologic and Nonhematologic 
Adverse Events Reported in ≥10% of All Treated Patients .......................... 28 
Table 2: 
Schedule of Assessments ............................................................................ 40 
Table 3: 
Analyte Listing .............................................................................................. 47 
Table 4:  Dose Level Reduction Guidelines ................................................................ 51 
Table 5:  Dose Modification Algorithms for Adverse Events Possibly Related to 
ABI-009 ........................................................................................................ 52 
 
LIST OF FIGURES 
Figure 1: Antitumor Activity of ABI-009 in Tumor Xenografts ...................................... 25 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine transaminase (SGPT) 
AML 
angiomyolipoma 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (SGOT) 
AUC 
area under the time-concentration curve 
BSA 
body surface area 
Cmax 
maximum plasma drug concentration 
Cmin 
minimum plasma drug concentration 
CBC 
complete blood count 
CCST 
clear cell sugar tumor 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DRT 
data review team 
DOR 
duration of response 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
electronic case report form 
EOS 
end of study 
EOT 
end of treatment 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 


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IND 
investigational new drug  
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
LAM 
intravenously 
lymphangioleiomyomatosis  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mL 
milliliter 
MRI 
magnetic resonance imaging 
MTD 
maximum-tolerated dose 
mTOR 
mammalian target of rapamycin 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PEComa 
perivascular epithelioid cell tumors  
PFS 
Progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PTEN 
protein tyrosine phosphatase 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
SPARC 
secreted protein acid rich in cysteine 
TBL 
total bilirubin level 
TSC 
tuberous sclerosis complex 
ULN 
upper limit of normal 
 
 


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Abbreviation or Term 
Definition/Explanation 
Advanced malignant 
PEComa 
Histologically confirmed malignant PEComa that is either 
metastatic or is locally advanced where surgery is not an option 
Study Day 1 
First day that protocol-specified IP is administered to the patient. 
End of Study 
 
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 
The date of the last dose of ABI-009 for an individual patient. 
End of Treatment 
Visit 
For a patient is when safety assessments and procedures are 
performed after the last treatment, which must occur at least 4 
weeks (± 7 days) after the last dose of ABI-009.  
Primary Analysis 
 
For this study will occur after all patients have either completed 
the study or completed 6 months of treatment. Patients who are 
still active at the time of the primary analysis may continue on 
study until disease progression or medication intolerance is 
observed. 
Follow-up Period 
 
The on-study time period after the End of Treatment Visit. 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 anticancer therapy. Follow up will 
continue approximately every 12 weeks (+/- 3 weeks), or more 
frequently as needed, until death, withdrawal of consent, or the 
study closes, whichever is the earliest. This evaluation may be 
made by record review and/or telephone contact. 
Efficacy Analysis 
Dataset  
 
All enrolled patients with measurable tumor per RECIST v1.1 at 
baseline who receive at least one does of ABI-009 and have a 
confirmed diagnosis of PEComa.  
Full Analysis Set 
All enrolled patients who receive at least one dose of ABI-009 
(treated population). 
Per-protocol Analysis 
Set 
All enrolled patients who do not have any prospectively defined 
protocol violations.  
Progression-free 
The time from the first dose date to the first observation of a 


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survival 
disease progression or death due to any cause.   
Overall survival 
The time from the first dose date to the date of death due to any 
cause. 
Overall response rate 
 
The proportion of patients who achieve a confirmed partial 
response or complete response per RECIST 1.1. Response 
rates based on an independent assessment by radiologists not 
involved in the conduct of the trial, and by the investigators 
assessment of response will be reported separately. 
Duration of response 
The time from when criteria of response are first met until the 
first observation of disease progression per RECIST v1.1 or 
death due to any cause, whichever comes first.  
 
 


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1. 
INTRODUCTION 
1.1. 
Malignant PEComa Disease Background 
Perivascular epithelioid cell tumors (PEComa) is a rare subset of soft tissue sarcomas 
recently recognized as a distinct entity by the World Health Organization [1, 2].  
PEComas are a family of rare mesenchymal tumors composed of histologically and 
immunohistochemically distinctive epithelioid cells. PEComas appear to arise most 
commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, and 
abdominopelvic sites. PEComas have a strong female predominance and can occur in 
a wide age range, with a median age of approximately 43 years.  
According to the most recent classification, the PEComa family of tumors include 
angiomyolipoma 
(AML), 
clear 
cell 
"sugar" 
tumor 
of 
the 
lung 
(CCST), 
lymphangioleiomyomatosis (LAM), and PEComa not otherwise specified (PEComa-
NOS), a term referring to less well-characterized PEComas of a variety of other 
anatomic origins [3, 4]. 
Most PEComas are benign, but there is a subset of aggressive PEComas, advanced 
malignant PEComas [5, 6], that may be either metastatic or locally advanced where 
surgery is not an option, for which there are currently no approved therapies, but a few 
case reports of clinical experience with unapproved treatments for this disease. The 
prognosis for patients with this patient subset is poor, with a median survival estimated 
to be 12-17 months following diagnosis of advanced disease, based on data combined 
from 
published 
retrospective 
analyses 
of 
very 
few 
patients 
and 
personal 
communications with clinicians who have treated malignant PEComa [3, 7-9]. These 
data included a mix of patients treated with chemotherapy, radiotherapy, and mTOR 
inhibitors. Therefore, a significant unmet need exists for effective therapies to treat this 
aggressive and life-threatening disease.  
Due to the extremely rare nature of malignant PEComa, there is very limited information 
on its incidence. Only one publication has provided an estimate of the incidence of 
malignant PEComa as 0.012-0.024/100,000 or 0.12-0.24/1,000,000 [10]. Based on this 
information, it is estimated that there are approximately 42-84 new patients per year in 
the USA with malignant PEComa. Based on limited information on survival of patients 
with malignant PEComa [3, 7-9], our estimate for prevalence of malignant PEComa is 
0.22-0.48/1,000,000 or approximately 77-168 patients in the USA. A recent report in 
2014 [11] reviewed 36 consecutive patients with a diagnosis of malignant PEComa at 
the Dana Farber Cancer Institute (DFCI) treated in a 5-year period between 2007-2012; 
the number of cases reported at DFCI is consistent with the estimate above. 
Treatment for Malignant PEComa  
Currently, no effective medical treatment has been approved for patients with malignant 
PEComa; therefore it represents a clear unmet medical need and requires the 
development of effective therapeutic interventions.  


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The primary treatment option for localized malignant PEComa cases is surgery. 
However, there is no curative therapeutic option once the disease has spread and it is 
usually fatal. The majority (~70%) of patients with localized primary malignant PEComas 
develop metastatic disease over a median follow-up of 1 year [3, 11] and nearly one fifth 
of the patients have metastatic disease at presentation [11]. Lung, liver, peritoneum, 
and bones were the most common sites of metastases in an observational study with 36 
patients [11]. There is no curative therapy once the disease has spread and it is usually 
fatal with a median survival of 12-17 months [3, 7-9].   
Currently, no effective medical treatment has been evaluated and approved in this 
indication. While there has not been a single prospective clinical trial in patients with 
malignant or metastatic PEComa, in a restrospective analysis assembled from isolated 
case reports of 18 patients with unresectable or metastatic malignant PEComas, the 
median overall survival was 16 months (range: 4 to 30 months) [3]. Chemotherapy and 
radiotherapy have not been shown to provide significant clinical benefit [3]. Neoadjuvant 
treatment has been utilized in a small number of cases usually reporting either 
progression or minimal evidence of efficacy in the resected tumor. The role of adjuvant 
therapy is also unclear [3]. In the metastatic setting, systemic chemotherapy has shown 
little efficacy, as there were no objective responses reported with the use of cytotoxic 
drugs, including doxorubicin, ifosfamide, paclitaxel, carboplatin, and epirubicin [3, 12]. 
In metastatic soft tissue sarcoma in general, cytotoxic therapy remains a standard 
treatment in both chemotherapy-naive and previously treated patients and single-agent 
doxorubicin is still an appropriate first-line chemotherapy option. As a single agent it 
resulted in an ORR of 5-18% and median OS of 7.0-12.0 months independent of the 
schedule of administration [13-15]. Several randomized trials compared doxorubicin-
based combinations such as high dose ifosfamide, imidazole carboxamide and/or 
gemcitabine versus doxorubicin single-agent. Response rates with combination were 
better than with single-agent doxorubicin (18-25% compared to 5-18%) [14, 16-18]. 
There were conflicting results in terms of PFS (2 to 8 months), only some trials reporting 
a benefit with the combination compared to doxorubicin alone, especially when high 
doses of both doxorubicin and ifosfamide were used [16]. Overall survival was not 
significantly improved but severity of AEs was significantly increased with the 
combination therapies [16]. Targeted therapies, such as ridaforolimus, imatinib, and 
pazopanib did not provide higher response rates in general soft tissue sarcomas (ORR 
1.9%, 2.2% and 6.3% respectively) [19-21]. Thus, despite its modest activity, 
doxorubicin has remained the drug used either in monotherapy or combination in adult 
soft tissue sarcomas for several years. Overactivation of the mTOR pathway has been 
reported and mTOR inhibitors have shown some efficacy in this indication, described in 
Section 1.3. 
Many benign PEComas such as renal AML and LAM are associated with the rare 
genetic mutation in the tuberous sclerosis complex (TSC). Patients presenting with both 
PEComa-NOS and TSC is even less common than TSC and LAM or AML [3]. Most 
malignant PEComas are sporadic and result from the loss of tumor suppressor gene 
TSC2 [22]. The mTOR pathway, which is inhibited by TSC1/TSC2 complex, is 
frequently deregulated in PEComas, making it a promising target for treatment. This 


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study will assess the safety and efficacy of a novel mTOR inhibitor, ABI-009, nab-
rapamycin, in patients with malignant PEComas.  
Histology 
Histologically, PEComas typically show a nested architecture, are characterized by a 
proliferation of usually epithelioid cells, which exhibit a focal association with blood 
vessels walls with subendothelial growth and a radial arrangement of tumor cells. The 
origin of perivascular epithelioid cells (PECs) remains unknown, with no normal 
counterpart identified so far. PECs generally have an epithelioid appearance, with a 
clear to granular eosinophilic cytoplasm, a round, centrally located nucleus and an 
inconspicuous nucleolus, although hyperchromasia and nuclear irregularity may be 
present. Ultrastructurally, PECs contain microfilament bundles with electron-dense 
condensation, numerous mitochondria and membrane-bound dense granules [22]. 
Immunohistochemically, PECs are usually characterized by positive staining for both 
melanocytic markers (HMB45,  MelanA/Mart1, and microphthalmia transcription factor) 
and muscle markers (smooth muscle actin, pan-muscle actin, and calponin), with 
desmin and S100 expression being less common. Some PEComas (particularly those 
with clear cytoplasm) lack expression of muscle markers. The most sensitive 
melanocytic marker for the diagnosis of PEComa is HMB-45 [4]. 
1.2. 
ABI-009 Background 
1.2.1. 
Rapamycin and Rapalogs 
Rapamycin is a crystalline powder with the empirical formula C51H79NO13 and a 
molecular weight of 914.17. Rapamycin is a protein kinase inhibitor that is approved for 
immunosuppression in renal transplant patients, and is under investigation as a cancer 
treatment. Rapamycin 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 [23]. 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 [24]. 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. Rapamycin and its analogs (rapalogs) 
function as allosteric inhibitors of mTORC1. Rapalogs are currently used in the 
treatment of advanced renal cell carcinoma and other tumors [25]. 
Numerous preclinical studies have reported the impact of different biomarkers involved 
in the mTOR pathway, on the efficacy of mTOR inhibitors, such as:  
• PI3K, TSC1, TSC2, PI3K, AKT, and PTEN gene mutations [26] 
• Phosphorylated p-AKT, p-S6, p-4EBP1 expression  [27] 
• biomarkers for the proliferation (Ki-67) and apoptosis (PARP) [25] 


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However, no clinical studies have confirmed the importance of these biomarkers as 
predictive factors of efficacy, except PI3K mutation in non PEComa tumors such as 
breast carcinoma [26]. 
Although rapamycin, an oral therapeutic, is an efficacious mTOR inhibitor, it has poor 
solubility, low oral bioavailability, and dose-limiting toxicity [23, 28]. Marketed rapamycin 
analogs are temsirolimus and everolimus. Temsirolimus, approved for the treatment of 
kidney cancer, is a prodrug of rapamycin and requires conversion by the CYP3A 
enzyme. Everolimus is approved for pediatric and adult patients with subependymal 
giant cell astrocytoma, for advanced hormone receptor-positive, HER2-negative breast 
cancer in combination with exemestane, progressive neuroendocrine tumors of 
pancreatic origin (PNETs), subependymal giant cell astrocytoma (SEGA) associated 
with tuberous sclerosis and advanced renal cell carcinoma after failure of treatment with 
sunitinib or sorafenib [29-33]. 
Oral rapamycin and currently available rapalogs induce common side effects including 
hypertension, maculopapular rash (75%), mucositis (50%), asthenia (40%), nausea 
(43%), thrombocytopenia, metabolic abnormalities and more rarely pneumonitis (8%, 
3% grade 3) sometimes fatal [34-36]. The most frequently occurring grade 3 or 4 
adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), 
and hypertriglyceridemia (6%) [37]. These side effects could lead to the discontinuation 
of the treatment in 60% of patients in some studies. 
1.2.2. 
ABI-009 (nab-Rapamycin) 
The novel nanoparticle albumin-bound rapamycin (nab-rapamycin, ABI-009) is freely 
dispersible in saline and is suitable for intravenous administration, and has produced 
both a favorable safety profile and evidence of efficacy in patients with metastatic solid 
tumors [38]. 
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 
[39]. This suggests that the nab formulation of rapamycin may also produce similar 
advantages over the standard rapamycin. 
The nab technology may enhance tumor penetration and accumulation via the albumin 
receptor-mediated (gp60) endothelial transcytosis. Albumin is highly soluble, has long 
plasma half-life, broad binding affinity, and accumulates in tumors, making it an ideal 
candidate for drug delivery [40, 41]. Albumin circulating in the bloodstream can interact 
with gp60 to initiate caveolae-mediated transcytosis to reach tumor cells [42, 43]. 
Indeed, nab-paclitaxel transcytosis across the epithelial monolayer was dependent on 
caveolae formation [44]. In accordance with these observations, at equal doses, nab-
paclitaxel showed greater selectivity to tumors compared with solvent-based paclitaxel, 
which is likely attributed to the biologically active ingredient albumin and lack of solvent 
[44]. 


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1.2.2.1. 
Preclinical Studies with ABI-009 
Preclinical primary pharmacology studies in vivo demonstrated significant antitumor 
activity of ABI-009 as a single agent administered intravenously at 40 mg/kg, 3 times 
weekly for 4 weeks, across different tumor xenograft models in nude mice (see Figure 1 
below), including breast, colorectal, multiple myeloma, and pancreatic cancer [45-49]. 
This dose level correlates to approximately 120 m g/m2 in human. These findings are 
consistent with published information on rapamycin as an mTOR inhibitor and the role 
of mTOR in tumor growth [50]. In addition, recent preclinical study has demonstrated 
that combination of ABI-009 with the Akt inhibitor perifosine induced synergistic 
antitumor activity in multiple myeloma [48]. 
Figure 1: 
Antitumor Activity of ABI-009 in Tumor Xenografts 
 
Preclinical pharmacokinetic (PK) studies in rats showed that intravenously administered 
ABI-009 exhibited linear PK with respect to dose and large volume of distribution (Vz), 
due to efficient tissue extraction of rapamycin from the central blood compartment [47]. 
Shortly after dosing, tissue rapamycin level was 3-5 fold higher than that of blood, 
indicating efficient extraction. The terminal half life of ABI-009 was long in rats, ranging 
from 13.4 - 25.8 hours and resulted in significant blood level at 48 hours (~10 ng/ml) 
and 120 hours (>1 ng/ml). Consistent with literature of rapamycin [51], excretion of ABI-
009 was primarily through the fecal route (68.57 - 69.99%) with minimum contribution 
from the renal route (7.73 - 8.84%). 
The safety and toxicity of ABI-009 were evaluated in a series of preclinical studies. In a 
GLP repeat-dose toxicity study in male and female rats, ABI-009 administered IV was 
well tolerated at doses up to 90 mg/kg (equivalent to 540 mg/m2 human dose) when 


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delivered every four days for 3 cycles. Nonclinical toxicology studies of ABI-009 showed 
no new or unexpected toxicity compared to what is already known for rapamycin and 
other rapalogs [52-54]. 
1.2.2.2. 
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 [38]. 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 was administered intravenously. The maximum tolerated 
dose was established at 100 mg/m2. 
Nineteen patients were evaluable for efficacy. One patient in the 45 mg/m2 (95 mg 
actual rapamycin 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 rapamycin 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%, Table 1). 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 serious AE, 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. In this clinical 
study, 16 of 26 patients (62%) had treatment-related adverse events (TRAEs) requiring 
a week dose delay: 
• 9 of 17 (53%) who received dose levels considered acceptable for future 
therapeutic usage, ie doses ≤ 100 mg/m2 : 
o 4 (57%) patients in the 45 mg/m2 dose cohort 
o 1 (33%) in the 56 mg/m2 dose cohort 
o 4 (57%) in the 100 mg/m2 dose cohort 


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• 7 of 9 (78%) who received higher dosage: 
o 2 (100%) in the 150 mg/m2 
o 5 (71%) in the 125 mg/m2 cohort 
The percentages of missing doses per dose level during the treatment period were: 
• 45 mg/m2: 20/86: 23% 
• 56 mg/m2: 2/21: 9.5% 
• 100 mg/m2: 11/72: 15.2% 
• 75 mg/m2: 7/27: 26% (75 mg/m2 dose level was given to 2 patients because of 
prior toxicity at 100 mg/m2; however this dosage was not part of the protocol, and 
as such has not been assessed) 
The total percentage of missing dose was 19.4% at dose levels considered acceptable 
for future therapeutic usage ie doses ≤ 100 mg/m2.  
Most of the missing doses (83%) occurred at day 15, corresponding to the 3rd 
administration within a cycle. Thus, the present study will examine 100 mg/m2 ABI-009 
given weekly for 2 weeks followed by a week off (Section 1.3.2). 


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Table 1:  Treatment-related Grade 1–4 Hematologic and Nonhematologic Adverse 
Events Reported in ≥10% of All Treated Patients 
 
1.2.2.3. 
ABI-009 (nab-Rapamycin) Pharmacokinetics (PK) 
ABI-009 produced a fairly dose proportional increase of Cmax and AUC across the dose 
range tested, and it significantly inhibited mTOR targets S6K and 4EBP1. 
ABI-009 has unique characteristics amongst the available mTOR inhibitors. The PK 
profile of rapamycin administered as ABI-009 is categorically different from those of the 
other oral or IV administered mTOR inhibitors. Intravenous infusion of ABI-009 results in 
high Cmax of rapamycin upon administration followed by a long half-life of approximately 
60 hrs that allows once weekly dosing. Peak levels of rapamycin after ABI-009 are well 
above 1000 ng/mL range that may have significant tumor penetration effect. Oral mTOR 
inhibitors such as rapamycin or everolimus have poor absorption with a high inter- and 
intra-patient variability and a poor safety profile that requires low basal levels (low 
ng/mL level) to be maintained over the course of treatment. Temsirolimus on the other 
hand is a prodrug of sirolimus (rapamycin) and as a result, high levels of rapamycin are 
 
MTD (100 mg/m2) n = 7 
All Treated Patients n = 26 
NCI CTCAE v 3.0 
G1 
G2 
G3 
G4 
G1 
G2 
G3 
G4 
Hematologic AEs, n 
(%) 
 
 
 
 
 
 
 
 
Anemia 
0 
0 
1 (14) 
0 
0 
3 (12) 
2 (8) 
0 
Hypokalemia 
1 (14) 
0 
0 
0 
5 (19) 
0 
1 (4) 
0 
Hypophosphatemia 
0 
1 (14) 
0 
0 
1 (4) 
2 (8) 
2 (8) 
0 
Hypertriglyceridemia 
1 (14) 
1 (14) 
0 
0 
2 (8) 
1 (4) 
1 (4) 
0 
Neutropenia 
1 (14) 
0 
0 
0 
2 (8) 
1 (4) 
1 (4) 
0 
Thrombocytopenia 
1 (14) 
4 (57) 
0 
0 
5 (19) 
6 (23) 
3 (12) 
1 (4) 
Nonhematologic AEs 
 
 
 
 
 
 
 
 
AST/SGOT 
0 
0 
0 
0 
1 (4) 
0 
2 (8) 
0 
Constipation 
0 
1 (14) 
0 
0 
1 (4) 
2 (8) 
0 
0 
Diarrhea 
1 (14) 
0 
0 
0 
3 (12) 
3 (12) 
0 
0 
Dyspnea 
0 
1 (14) 
1 (14) 
0 
1 (4) 
2 (8) 
1 (4) 
0 
Fatigue 
1 (14) 
4 (57) 
0 
0 
1 (4) 
6 (23) 
0 
0 
Infection, oral cavity 
1 (14) 
1 (14) 
0 
0 
3 (12) 
2 (8) 
0 
0 
Mucositis/stomatitis 
3 (43) 
2 (29) 
0 
0 
7 (27) 
3 (12) 
0 
0 
Nausea 
1 (14) 
1 (14) 
0 
0 
3 (12) 
2 (8) 
0 
0 
Rash 
1 (14) 
0 
0 
0 
4 (15) 
2 (8) 
0 
0 
Weight loss 
0 
0 
0 
0 
1 (4) 
2 (8) 
0 
0 
 


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not achieved (< 100 ng/mL) [55]. The administration of ABI-009 led to a much higher 
exposure to rapamycin (sirolimus) as compared to sirolimus from temsirolimus (Cmax 
almost 50 fold higher, AUC almost 12 fold higher for ABI-009) or everolimus (Cmax 50-70 
fold higher, AUC 85-200 fold higher for ABI-009) [38, 55]. Unlike with other mTOR 
inhibitors, micromolar concentrations are reached and maintained for several hours with 
ABI-009 which could potentially circumvent acquired resistance to mTOR inhibitors via 
retroactivation of AKT by TORC2 [56, 57].  The high exposure achieved with ABI-009 
with acceptable safety profile could be highly relevant to the treatment of aggressive 
cancers such as malignant PEComas. 
1.3. 
Rationale for the Study 
1.3.1. 
Rationale for the Use of ABI-009 in Advanced Malignant PEComas 
The rationale behind mTOR inhibitor use in PEComas lies in the fact that both classic 
PEComas and PEComa-NOS have been shown to frequently harbor mutations in the 
TSC1 and/or TSC2 genes, which regulate cell proliferation via the mTOR pathway [58]. 
Tumors of the PEComa family are rare and usually occur sporadically. 
Lymphangioleiomyomatosis and AML also are seen at high frequency in patients with 
TSC, a disorder caused by mutation of TSC1 or TSC2, for which the gene products 
negatively regulate mTORC1 through inhibition of the mTOR kinase activator, RHEB 
[58]. Both TSC1 and TSC2 gene products are involved in multiple cellular pathways, 
including regulation of cell proliferation, migration and differentiation through inhibition of 
the 
Rheb/mTOR/p70S6 
kinase-signaling 
pathway 
[58]. 
Inactivation 
of 
the 
tuberin/hamartin complex in TSC thus leads to the activation of mTOR and the 
phosphorylation of p70S6K and ribosomal protein S6, and further promotes translational 
initiation and cell growth. This mTOR pathway is reported to be up regulated not only in 
TSC-associated AML, but also in sporadic AML or PEComas [59]. A high frequency of 
loss of heterozygosity (LOH) in TSC2 gene is found in sporadic PEComas and sporadic 
classic renal and hepatic AMLs, with much lower LOH observed for TSC1 [60]. In a 
recent study, activation of mTORC1 pathway, manifested by increased phosphorylated 
p70S6K and decreased phospho-Akt levels, was observed in 100% non-TSC AMLs and 
93% of extra-renal PEComas [61]. 
Initial trials of these agents in the classic PEComas (AML, LAM) have led to a number 
of meaningful responses [4, 62], sparking interest in their use for advanced or recurrent 
PEComa-NOS. Clinical benefits have been observed in a number of PEComa case 
studies using rapamycin [5, 63], temsirolimus [64], and everolimus [65], although these 
responses have not been uniform. Wagner et al reported a short series of 3 patients 
treated with rapamycin for metastatic malignant PEComas. Radiographic responses 
were observed in all 3 patients. Loss of TSC2 protein expression and evidence of 
baseline mTORC1 activation was found in all patients. Homozygous loss of TSC1 was 
identified in one PEComa [5]. Dickson et al reported on the use of rapamycin in the 
treatment of 5 consecutive patients with extrarenal nonpulmonary PEComas with 3 
CRs, 1 PR, and 1 case of progression [6].  In a retrospective study, the Royal Marsden 
Hospital reported that a population of 10 patients treated with either temsirolimus or 
rapamycin showed promising response rate but short remission duration [9]. It is 


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noteworthy that in a published clinical case, malignant PEComa tumors deemed 
inoperable or with borderline resectability achieved sufficient bulky tumor shrinkage with 
neoadjuvant rapamycin for a surgical resection. The option of neoadjuvant treatment 
may be considered for selected high-risk patients who can tolerate an mTOR inhibitor 
[63]. 
Additional justification for treating patients with malignant unresectable PEComa with 
ABI-009 instead of irradiation or doxorubicin-based chemotherapy: The available 
molecular and clinical evidence provides a strong rationale for using mTOR inhibitors in 
this disease. Thus participation in this clinical trial will be a reasonable option for many 
patients with advanced malignant PEComa. Most oncologists with expertise in sarcoma 
favor this approach since the disease is considered to be relatively insensitive to 
systemic chemotherapy and radiotherapy. Radiotherapy can be considered in selected 
cases, but may not be recommended depending on the location and/or extent of the 
tumor. Prior treatment with chemotherapy or radiotherapy would not exclude a patient 
from enrolling in the study and remain options at the discretion of the patient’s treatment 
team. 
The mechanisms of resistance to mTOR inhibition in malignant PEComa remain an 
important area for research [66, 67]. TFE3 gene rearrangement was recently reported in 
a small number of PEComas with no evidence of TSC2 mutation, which is suggested to 
cause resistance to mTOR inhibition, but this would need to be confirmed in a 
prospective study [68]. In addition, although rapamycin and rapalogs have shown some 
efficiency in the treatment of malignant PEComas, they induce AEs that can lead to 
treatment interruption, and thus compromising efficacy, and impact the quality of life, 
and lesions will typically regrow when the inhibitor is discontinued. More importantly, no 
formal clinical study has been conducted to investigate mTOR inhibitors safety and 
efficacy. These data clearly support the development of new mTOR inhibitors in an 
open study in the treatment of malignant PEComa.  
It is estimated that 85% to 90% of the advanced malignant PEComas are metastatic 
and 10% to up to 15% are localized but unresectable. Allowing enrollment for both of 
these 2 subgroups of patients will permit assessing the efficacy of ABI-009 for response 
rate.  
With favorable systemic safety at doses of 100 mg/m2 given weekly IV observed in the 
phase 1 study, therapy with ABI-009 should result in manageable adverse events and 
provide significant therapeutic benefit to patients with malignant PEComas. 
1.3.2. 
Rationale for the Schedule of Administration of ABI-009 
A slightly different schedule of administration has been selected in the present study 
than was studied in the initial Phase 1 study CA401. In this study, 2 of 3 weekly 
schedule will be used instead of 3 of 4 weeks as in phase 1 clinical study CA-401.  
The rationale for the modification to the schedule of administration of a dose of 100 
mg/m2 is to further improve the tolerance of ABI-009. As discussed in Section 1.2.2.2, 
19.4% of doses were missed at doses ≤100 mg/m2. Most of the missing doses (83%) 
occurred at day 15, corresponding to the 3rd administration within a cycle. Thus, the 


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present study will examine 100mg/m2 ABI-009 given weekly for 2 weeks followed by a 
week off. This change in schedule will not substantially impact the total drug received by 
the patients. In a period of 6 months (24 weeks) of treatment, the 2/3 schedule will allow 
16 administrations, while the 3/4 schedule will allow 18 administrations.   
 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
To investigate the efficacy of the mTOR inhibitor ABI-009 in advanced malignant 
PEComa.  
2.1.2. 
Secondary Objectives 
The objectives are to further investigate the efficacy and safety of IV ABI-009 100 
mg/m2 given weekly for 2 of 3 weeks in patients with advanced malignant PEComa.  
2.1.3. 
Exploratory Objectives 
Exploratory Objectives  
• To evaluate investigator assessed ORR 
• To evaluate pharmacokinetic/pharmacodynamic relationships for safety and/or 
efficacy endpoints  
• To evaluate tumor biomarkers: 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
The primary endpoint is objective overall response rate (ORR), as determined by 
independent radiologic assessment using Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. 
2.2.2. 
Secondary Endpoints 
The secondary endpoints are duration of response (DOR), progression-free survival 
(PFS) rate at 6 months, PFS, overall survival (OS), and safety/tolerability. 
• DOR, PFS rate at 6 months, median PFS, and OS will be assessed separately in 
subgroups of patients with metastatic disease and locally advanced disease. 
Patients in the locally advanced tumor subgroup may be clinically indicated to 
receive surgery if there is sufficient tumor shrinkage, which could introduce a bias 
in the assessment of the DOR, PFS rate at 6 months, median PFS, and OS. 
Safety will be analyzed in all treated patients. 
2.2.3. 
Exploratory Endpoints 
• Investigator assessed ORR 
• Pharmacokinetic/pharmacodynamic relationships for safety and/or efficacy 
endpoints  


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• To evaluate tumor biomarkers: 
o Blood samples will be obtained for cell-free plasma DNA collection 
(pretreatment, Cycle 4/Day 1, and post-treatment) for all patients.  
 Molecular analysis of cell-free plasma DNA assay using next-generation 
sequencing to assess the prevalence of mutations identified in the primary 
tumor sample over time as a measure of response to therapy.  
o Tumor biopsy mutation analysis to assess resistance mechanisms. Pre-
treatment tumors (archival or fresh tissue biopsies) are required for all 
patients on this study to confirm diagnosis. This sample will also be used for 
baseline mutational analysis. In addition, an optional tumor biopsy will be 
collected for patients who provide additional consent at the end of treatment 
and/or if a patient experiences progression while on study. 
 


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3. 
OVERALL STUDY DESIGN  
3.1. 
Study Design 
This study is a prospective, single arm, phase 2, open label, multi-institutional study to 
determine the efficacy and safety profile of intravenous ABI-009 in patients with 
advanced malignant PEComa.  
The study will be conducted in compliance with the International Council on 
Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use/ GCP and applicable regulatory requirements. 
This study will be conducted at approximately 9 sites in the United States. 
3.2. 
Study Duration  
The duration of enrollment for this study will last approximately 24 months. A cycle will 
consist of 3 weeks, with ABI-009 given weekly for 2 weeks followed by a week of rest.  
Treatment will continue until disease progression or unacceptable toxicity. 
It is anticipated that each study patient will be on study for approximately 2 weeks of 
screening, approximately 6 months of treatment and 4 weeks of safety follow up. The 
total duration of the study is expected to be approximately 32 months. 
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 for an 
individual patient 
End of Treatment Visit for a patient is when safety assessments and procedures are 
performed after the last treatment, which must occur at least 4 weeks (± 7 days) after 
the last dose of ABI-009.  
Primary analysis for this study will occur after all patients have either completed the 
study or completed 6 months of treatment. Patients who are still active at the time of the 
primary analysis may continue on study until disease progression or medication 
intolerance is observed. 
Primary Completion is the time when the last patient is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis.  
Follow-up period is the on-study time period after the EOT Visit. 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 anticancer therapy. Follow-up will 
continue approximately every 12 weeks (+/- 3 weeks), or more frequently as needed, 


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until death, withdrawal of consent, or the study closes, whichever is the earliest. This 
evaluation may be made by record review and/or telephone contact. 
The final patient’s last visit for the study will be defined as whichever of the following 
represents the last time point: 
• When the last patient on study has completed their Safety follow-up visit, or 
• When the last patient on study has documented toxicities to ABI-009 and the 
toxicity has resolved, returned to baseline or is deemed irreversible after the 
Safety follow-up visit or 
• When the last patient completes or discontinues the follow-up phase 


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4. 
STUDY POPULATION 
4.1. 
Number of Patients 
The anticipated enrollment into this study will be at least 30 evaluable patients. The 
rationale for the number of patients is detailed in Section 10. 
Investigators will be expected to maintain and submit every other week a screening log 
of all potential study candidates that includes limited information about the potential 
candidate, date, and outcome of the screening process (eg, enrolled into study, reason 
for ineligibility, or refused to participate).   
Investigators will also be expected to document the reasons for which any patient 
enrolled on the trial with locally advanced malignant PEComa disease is not a suitable 
candidate for local treatment (eg, surgery or irradiation).   
Before any study-specific procedure, the appropriate written informed consent must be 
obtained (see Section 13.1). 
If for a given patient, the appropriate tumor tissue is not made available for centralized 
retrospective confirmation of malignant PEComa tumor type, this patient may be 
replaced. Additional patients may be enrolled if the Sponsor determines that the 
minimum required number of patients with evaluable tissue samples have not been 
enrolled. 
4.2. 
Inclusion Criteria  
A patient will be eligible for inclusion in this study only if all of the following criteria are 
met: 
1. Patients must have a histologically confirmed diagnosis of malignant PEComa 
that is either metastatic or locally advanced and for which surgery is not a 
recommended option. 
2. Patients must have available tumor block along with the corresponding 
pathology report (or approximately 30 unstained slides, with a minimum of 16 
slides), and/or fresh biopsy to allow retrospective centralized confirmation of 
malignant PEComa and for mTOR pathway analysis and biomarker analysis.  
3. Patients must have one or more measurable target lesions by CT scan or MRI. 
Measurable disease by RECIST v1.1.  
4. Patients must not have been previously treated with an mTOR inhibitor. 
5. Prior treatment (investigational or other), chemotherapy, radiotherapy, surgery, 
or other therapeutic agents (except mTOR inhibitors) is allowed, if completed 
after 5 half-lives or ≥28 days prior to enrollment, whichever is shorter. 
6. Eligible patients, 18 years or older, with Eastern Cooperative Oncology Group 
(ECOG) performance status 0 or 1. 


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7. Patients must have the following blood chemistry levels at screening (obtained 
≤14 days prior to enrollment (local laboratory): 
a. total bilirubin ≤1.5 x upper limit of normal (ULN) mg/dl 
b. AST ≤2.5 x ULN (≤5 x ULN if attributable to liver metastases) 
c. serum creatinine ≤1.5 x ULN 
8. Adequate biological parameters as demonstrated by the following blood counts 
at screening (obtained ≤14 days prior to enrollment, local laboratory): 
a. Absolute neutrophil count (ANC) ≥1.5 × 109/L; 
b. Platelet count ≥100,000/mm3 (100 × 109/L); 
c. Hemoglobin ≥9 g/dL.  
9. Serum triglyceride <300 mg/dL; serum cholesterol < 350 mg/dL. 
10. 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. 
11.  Life expectancy of >3 months, as determined by the investigator. 
12. Ability to understand and sign informed consent. 
13. Willingness and ability to comply with scheduled visits, laboratory tests, and 
other study procedures. 
4.3. 
Exclusion Criteria  
A patient will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. Patients with lymphangioleiomyomatosis (LAM) are excluded.  
2. Known active uncontrolled or symptomatic CNS metastases. A patient with 
controlled and asymptomatic CNS metastases may participate in this study. As 
such, the patient must have completed any prior treatment for CNS metastases 
≥28 days (including radiotherapy and/or surgery) prior to start of treatment in this 
study and should not be receiving chronic corticosteroid therapy for the CNS 
metastases. 
3. Active gastrointestinal bleeding. 


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4. Pre-existing thyroid abnormality is allowed provided thyroid function can be 
controlled with medication. 
5. Uncontrolled serious medical or psychiatric illness. Patients with a “currently 
active” second malignancy other than non-melanoma skin cancers, carcinoma in 
situ of the cervix, resected incidental prostate cancer (staged pT2 with Gleason 
Score ≤6 and postoperative PSA <0.5 ng/mL), or other adequately treated 
carcinoma-in-situ are ineligible. Patients are not considered to have a “currently 
active” malignancy if they have completed therapy and are free of disease for ≥1 
year). 
6. Liver-directed therapy within 2 months of enrollment. Prior treatment with 
radiotherapy (including radio-labeled spheres and/or cyberknife, hepatic arterial 
embolization (with or without chemotherapy) or cyrotherapy/ablation) is allowed if 
these therapies did not affect the areas of measurable disease being used for 
this protocol. 
7. Recent infection requiring systemic anti-infective treatment that was completed 
≤14 days prior to enrollment (with the exception of uncomplicated urinary tract 
infection or upper respiratory tract infection). 
8. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate 
therapy. 
9. Unstable coronary artery disease or myocardial infarction during preceding 6 
months.     
10. Receiving any concomitant antitumor therapy. 
11. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary 
hypertension. 
12. 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.   
13. Known Human Immunodeficiency Virus (HIV). 
14. Active Hepatitis B or Hepatitis C. 
 
 


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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 
Assessment a 
Screening b 
(Day -14 to - 1) 
Cycle 1 through Last Cycle 
(Treatment Period) 
End of Treatment 
(EOT) Visit d 
Follow-up 
Period e 
Day 1 c 
Day 8 
General Assessments, Biomarkers, PK samples 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Examination 
X 
X 
 
X 
 
Vital Signs, Height and Weight  
X 
X f 
X f 
X f 
 
BSA Calculation 
 
X m 
 
 
 
Prior/Concomitant Medication Evaluation g 
X 
X 
X 
Until 28 days after 
the last dose of IP 
 
Prior/Concurrent Procedures Evaluation g 
X 
X 
X 
Until 28 days after 
the last dose of IP 
 
ECOG PS 
X 
X 
 
X 
 
Pregnancy Test h 
X 
 
 
X 
 
ECG (12 lead) i 
X 
X 
X 
 
 
Survival status  
 
 
 
 
X 
Pre-treatment tissues (archival or fresh) (mandatory) j 
X 
 
 
 
 
Tumor biopsy for Biomarkers  k 
X 
Upon disease progression and/or end of last dose of IP 
Blood Sample for Biomarkers   
X 
Cycle 4/D1 and Upon disease progression and/or end of last dose of IP 
Blood Sample for Rapamycin (PK) l 
 
Pre-treatment 
and at 0.5, 1, 2, 4 
hrs post-
treatment 
Pre-treatment 
and at 0.5, 1, 2, 4 
hrs post-
treatment 
 
 
Adverse Events  
Continuous starting from signing of Informed Consent until 28 days after last dose of IP 


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Assessment a 
Screening b 
(Day -14 to - 1) 
Cycle 1 through Last Cycle 
(Treatment Period) 
End of Treatment 
(EOT) Visit d 
Follow-up 
Period e 
Day 1 c 
Day 8 
ABI-009 Dosing 
 
X 
X 
 
 
Local Laboratory Assessments 
Clinical Chemistry Panel 
X 
X 
 
X 
 
CBC, Differential, Platelet Count 
X 
X 
X 
X 
 
PT, PTT, INR 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
Thyroid function 
X 
X 
 
 
 
HIV, HBV sAg, HBV cAb, HCV Ab 
X 
 
 
 
 
Fasting Lipids 
X 
X n 
 
 
 
Imaging and Efficacy Assessments 
CT/MR o 
X 
Every 6 weeks after C1 D1 for the 
first year, then every 12 weeks 
thereafter 
X 
 
a. 
Unless otherwise specified, visits must occur within ± 2 days of the planned visit date. 
b. 
Screening evaluations to be obtained ≤14 days prior to enrollment unless specified otherwise. 
c. 
Day 1 evaluations can be omitted if screening evaluations are performed within 72 hours of Cycle 1 Day 1. 
d. 
End of Treatment Visit must occur at least 4 weeks (± 7 days) after the last dose of ABI-009. 
e. 
Follow-up for survival and initiation of anticancer therapy can be performed by telephone contact every 12 weeks (+/- 3 weeks) or more frequently if needed, from EOT Visit. 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 anticancer therapy. This 
evaluation may be made by record review and/or telephone contact. 
f. 
Vitals and weight only. 
g. 
Prior: record all medications taken and procedures done ≤ 28 days prior to screening; Concomitant: any medications or procedures after the signing of informed consent. 
h. 
For females of childbearing potential only.  A serum β-hCG pregnancy test must be performed to assess patient eligibility at screening prior to first IP administration (negative results 
required for IP administration).  Urine pregnancy test will be performed at EOT Visit (can be done locally) and as clinically indicated as per institutional guidelines. 
i. 
ECG to be monitored at screening, Cycle 1 Day 1 and Day 8, and thereafter on Day 1 of every treatment Cycle. In each case ECG is to be monitored during infusion around the 30 min 
time point after start of infusion to coincide with the end of infusion period which lasts 30 minutes (+/- 10 min). 
j. 
Ensure the surgical pathology report is submitted with tumor tissue sample (either tumor block or unstained slides [min 6]). 
k. 
Biopsy tumor sample: formalin-fixed, paraffin-embedded (FFPE) tumor tissue or unstained slides from biopsy will be collected (tumor blocks are preferred – refer to Instruction Sheet 
for details). Screening tumor tissue (fresh/archival) required for biomarker analysis for all patients. On study tumor tissue collection is optional only for patients who provide additional 
consent. 
l.         PK samples to be taken only at Cycle 1 on Day 1 and Day 8 (pre-treatment and at 0.5, 1, 2, and 4 hrs ( +/- 10 min) post-treatment) and in Cycle 2 Day 1, when only a pre-treatment 
sample is required. 
m. 
Calculated ONLY on C1/D1; to be recalculated only if the weight changes by > 10% in subsequent cycles. 
n. 
Every even numbered cycle starting with Cycle 2, eg C2, C4, C6, etc. 


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o. 
Screening CT/MRI scans must be performed within 28 days prior to study day 1, preferably as close to the day of enrollment as possible. Tumor evaluation by contrast-enhanced CT 
or MRI of the chest, abdomen, and pelvis will be performed during screening; every 6 weeks (± 3 days after C1D1 for the first year then every 12 weeks (± 7 days) thereafter until 
disease progression. EOT visit CT/MRI should be performed only for those patients that discontinue treatment for a reason other than disease progression per RECIST 1.1. If an initial 
observation of objective response (CR or PR) is made, a confirmation scan should be done at 6 weeks after initial observation.


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6. 
PROCEDURES 
6.1. 
Screening Evaluations 
This study will be conducted at approximately 10 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. Adverse Events are 
to be collected for a patient once they are signed the informed consent. The patients’ 
tumor samples will be tested to confirm diagnosis and for biomarker analyses after 
informed consent form has been signed.   
Screening evaluations will be performed for all patients to determine study eligibility.  
These evaluations must be obtained ≤14 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. 
• Demographics (if allowed by local regulations, date of birth, sex, race, and 
ethnicity) 
• Physical examination as per standard of care (including physical exam, 
medical/cancer history, ECOG performance status assessment, height, 
weight)  
• Prior/concomitant medication evaluation: all medications taken ≤28 days prior 
to screening  
• Prior/concurrent procedures evaluation: all procedures done ≤28 days prior to 
screening 


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• Vital signs (eg, blood pressure, pulse, respiration rate, temperature) 
• ECG   
• Informed consent signed to collect for pre-treatment tumor sample (archived 
or fresh) along with pathology report for diagnosis confirmation and biomarker 
study for all patients  
• Adverse event assessment 
• Local Laboratory Assessments: chemistry, complete blood count (CBC), 
differential, platelet count, coagulation, urinalysis, thyroid function, pregnancy 
test (women of child-bearing potential, includes tubal ligations), HIV, hepatitis 
B surface antigen, hepatitis C antibody, fasting lipids 
• Urinalysis (a urine dipstick may be used) 
• CT or MRI, must be performed within 4 weeks prior to study day 1, preferably 
as close to the day of enrollment as possible 
A patient is considered enrolled 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 14 days of study day 1, 
unless specified otherwise in the study procedures listed in Section 5. Once eligibility is 
confirmed, a site representative will complete and fax a patient eligibility criteria 
worksheet/tumor biopsy reference form to an AADi representative. The AADi 
representative will acknowledge receipt of the paperwork and confirm enrollment for that 
individual patient.  
6.2. 
Treatment Period 
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. Patients will 
continue therapy until disease progression or unacceptable adverse events. 
6.2.1. 
Day 1 Assessment 
The following assessments will be performed on Day 1 of each cycle, unless otherwise 
specified: 
• Physical examination  
• Weight assessment 
• BSA calculation (Calculated ONLY on C1/D1; to be recalculated only if the 
weight changes by > 10% in subsequent cycles  
• Concomitant medication and procedures evaluation  
• Vital signs (temperature, systolic and diastolic blood pressure, and pulse) 
• ECOG performance status 


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• ECG (12-lead ECG is to be conducted during infusion around the 30 min time 
point after start of infusion to coincide with the end of infusion period which 
lasts 30 minutes [+/- 10 min]). Day 1 ECG is conducted for every cycle. 
• Clinical chemistry panel (including but not limited to sodium, potassium, 
chloride, glucose, alkaline phosphatase (ALP), AST/SGOT, ALT/SGPT, 
serum albumin) 
• CBC, differential and platelet count 
• Thyroid function 
• Fasting lipids (every even numbered cycles starting with Cycle 2) 
• Adverse Event assessment 
• Pharmacokinetics assessment (only on Cycle 1 Day 1 at pre-treatment and at 
0.5, 1, 2, 4 hrs post-treatment and Cycle 2 Day 1 at pre-treatment only) 
Day 1 evaluations for Cycle 1 may be omitted if screening evaluations are performed 
within 72 hours of Cycle 1 Day 1. Laboratory assessments: chemistry, hematology, 
coagulation, urinalysis, pregnancy test (women of child-bearing potential, includes tubal 
ligation) (see Table 3 for analyte listing). 
6.2.2. 
Day 8 Assessment 
The following assessments will be performed on Day 8 of each cycle, unless otherwise 
specified: 
• Concomitant medication and procedures evaluation 
• Vital signs 
• CBC, differential and platelet count 
• Adverse Event assessment 
• Pharmacokinetics assessment (only on Cycle 1 Day 8 pre-treatment and at 
0.5, 1, 2, 4 hrs post-treatment) 
• ECG (12-lead ECG is to be conducted during infusion around the 30 min time 
point after start of infusion to coincide with the end of infusion period which 
lasts 30 minutes [+/- 10 min]). Day 8 ECG is conducted only on Cycle 1. 
 
6.2.3. 
Response Assessment  
Tumor response will be assessed by CT or MRI scan of the chest, abdomen, and pelvis; 
image preparation and evaluation will follow the specifications provided in the RECIST 
version 1.1. The same modality (CT or MRI) must be used at screening and throughout 
the study.  
CT/MRI scans to be performed at the following frequency: 
• ≤4 weeks prior to C1D1 (screening) 


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• followed by every 6 weeks after C1D1 for the first 1 year (± 3 days) 
• followed by every 12 weeks (± 7 days) thereafter until disease progression. 
End of Treatment Visit CT/MRI should be performed only for those patients 
that discontinue treatment for a reason other than disease progression. 
 
An unscheduled scan for suspected disease progression may be performed at any time. 
However, adherence to the planned imaging schedule is critical regardless of dose 
delays or unscheduled or missed assessments. Scans will be submitted to an 
independent central imaging laboratory for assessment by RECIST 1.1 and for 
determination of measurable disease. Determination of disease progression for clinical 
management of patients on study will be assessed at the local site. If an initial 
observation of objective response (CR or PR) is made, a confirmation scan should be 
done at 6 weeks after initial observation.  
At the time of disease progression, if a biopsy is performed, a tumor sample will be 
collected and sent to the central laboratory, if available. Ensure that the surgical 
pathology report is submitted with the tumor tissue sample. Refer to the Instruction 
Sheet for tissue handling instructions for processing and shipping details.   


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Table 3: 
Analyte Listing 
Chemistry 
Hematology 
Coagulation 
Urinalysis 
Other Labs 
Sodium 
WBC 
PT 
Specific gravity Pregnancy test 
Potassium 
RBC 
PTT 
pH 
ABI-009 PK (central) 
Bicarbonate 
Hemoglobin 
INR 
Blood 
TSH, T3, T4 
Chloride 
Hematocrit 
 
Protein 
HIV 
Total protein 
MCV 
 
Glucose 
HBV sAg 
Albumin 
MCH 
 
Ketones 
HBV cAb 
Calcium 
MCHC 
 
Microscopic 
HCV Ab 
Magnesium 
RDW 
 
 
Total Cholestrol  
Phosphorus 
Platelets 
 
 
HDL 
Glucose 
Differential: 
 
 
LDL 
BUN 
-Neutrophils 
 
 
Triglyceride 
Creatinine 
-Lymphocytes 
 
 
Biomarker 
development (central) 
Total bilirubin 
-Monocytes 
 
 
 
Alkaline phosphatase -Eosinophils 
 
 
 
AST (SGOT) 
-Basophils 
 
 
 
ALT (SGPT) 
 
 
 
 
Amylase 
 
 
 
 
Lipase 
 
 
 
 
 
6.3. 
End of Treatment Visit Assessment 
Patient participation is complete after the EOT Visit. The EOT Visit is a safety follow-up 
visit that is to be performed at least 4 weeks (+ 7 days) after the last dose of ABI-009. 
All efforts should be made to conduct this visit. If it is not possible to conduct the EOT 
Visit, documentation of efforts to complete the visit should be provided. 
The following procedures will be completed at the EOT Visit as designated in the 
Schedule of Assessments (Section 5): 
• Physical examination (including physical exam, ECOG Performance Status 
assessment, weight)  
• Vital signs (eg, blood pressure, pulse, respiration rate, temperature) 
• Laboratory assessments: chemistry, CBC, differential, platelet count, 
pregnancy test (women of child-bearing potential, includes tubal ligations) 
• Imaging Assessment: CT/MRI is to be performed at the end of study visit only 
for those patients that discontinue treatment for a reason other than disease 
progression per RECIST v1.1  


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6.4. 
Follow-up Period for Survival and Initiation of Anticancer Therapy  
Post-treatment survival time and any subsequent anticancer therapy information status 
will be monitored approximately every 12 weeks (+/-3 weeks) from EOT Visit or more 
frequently as needed, until death, withdrawal of consent, or the study closes, whichever 
is earliest.  This evaluation may be by record review and/or telephone contact.  
6.5. 
Pharmacokinetic Study 
A PK study of rapamycin will be performed with limited PK sampling on all patients in 
this phase 2 study. Blood samples will be obtained during Cycle 1 Day 1 (C1D1) 
immediately predose (before infusion), 0.5 hr (immediately before termination of 
infusion), 1 hr, 2 hrs, and 4 hrs; during Cycle 1 Day 8 (C1D8) immediately predose 
(before infusion), 0.5 hr (immediately before termination of infusion), 1 hr, 2 hrs, and 4 
hrs, and on Cycle 2 Day 1 (C2D1) immediately predose (before infusion). All samples 
should be collected within a window of +/- 10 minutes.  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 (0.5 hour) is collected immediately before the infusion 
is stopped. If the duration of infusion is changed, the sample should be collected 
immediately before termination of the infusion.  
Whole-blood samples will be collected in EDTA tubes for determination of rapamycin in 
a central laboratory. 
Time Recording:   
• The exact clock time for the start and end of infusion must be recorded. 
• The exact clock time of each collection must be recorded. 
6.6. 
Biomarker Development  
The key objective of the tumor molecular profiling is to identify specific markers that are 
predictive of response to ABI-009. The key objective of the biomarker blood sampling is 
to investigate whether blood sampling can serve as a “liquid biopsy” to monitor disease 
progression. 
o Blood samples will be obtained for cell-free plasma DNA collection 
(pretreatment, Cycle 4/Day 1, and post-treatment) for all patients:  
 Molecular analysis of cell-free plasma DNA assay using next-
generation sequencing to assess the prevalence of mutations identified in 
the primary tumor sample over time as a measure of response to therapy.  
o Tumor biopsy mutation analysis to assess resistance mechanisms. Pre-
treatment tumors (archival or fresh tissue biopsies) are required for all 
patients on this study to confirm diagnosis. This sample will also be used for 
baseline mutational analysis. In addition, an optional tumor biopsy will be 
collected for patients who provide additional consent at the end of treatment 
and/or if a patient experiences progression while on study. 
 


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Tumor biopsies are to be collected and pharmacodynamic changes analyzed to 
determine the effect of the drug on target(s) in the tumor as well as to potentially 
analyze molecular mechanisms associated with acquired resistance.  
o Exome sequencing using the Oncopanel test (BWH Pathology Department, 
CLIA certified) of approximately 300 genes will be performed to assess 
mutations in all the known mTOR pathway genes, including but not limited to 
PIK3CA, TSC1, TSC2, AKT, PTEN, MTOR, and RHEB.  Rationale: TSC1 and 
TSC2 mutations are known to occur at high frequency in PEComa. 
- Evaluate correlation to clinical response to the therapy. 
- Test the correlation between biopsy and circulating DNA. 
o FISH (fluorescence in-situ hybridization) analysis of translocations in TFE3. 
TFE3 translocations are known to occur at low frequency in PEComa. These 
studies will be performed centrally in a laboratory that is CLIA certified. 
o Immunohistochemistry on relevant pathway markers, including but not 
limited to: 
- phosphoproteins p-AKT, p-S6, p-4EBP1, SPARC  
- proliferation marker, such as Ki-67 
- apoptosis  marker, such as PARP 
 Post-treatment (progression) samples will be analyzed by similar 
exome sequencing as above, to search for causes of resistance, 
including secondary mutations and genomic amplification or deletion 
events. 


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7. 
DESCRIPTION OF STUDY TREATMENTS 
7.1. 
ABI-009 Dosage, Administration, and Schedule 
Treatment cycles are 21 days in duration and patients are treated until disease 
progression or unacceptable toxicities. Patients will receive ABI-009 100 mg/m2 (IV 
infusion over 30 minutes, +/- 10 min) weekly for 2 weeks followed by a week of rest (2/3 
weekly schedule). The schedule 2 weeks out of a 3 weekly schedule will allow the 
patient to have 1 week rest, when most of the toxicities occur, based on experience in 
the phase 1 study of ABI-009 (Protocol CA401) [38]. In terms of dose intensity within 6 
months (24 weeks), the 2 out of 3 weekly schedule will consist of 16 administrations 
compared to 18 administrations with the prior 3 out of 4 weekly schedule. This reflects a 
global dose intensity reduction of 11% when comparing the 2 schedules. Two dose 
reduction levels are allowed: 75 mg/m2 and 56 mg/m2. 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. 
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 +/- 2 days from the scheduled date. Prior to ABI-009 administration on 
Day 1 of each cycle, patients must meet the following hematological requirements: 
• ANC ≥ 1.5 x 109/L 
• Platelet count ≥ 100 x 109/L 
• Hemoglobin ≥9 g/dL 
The treatment will be on hold up to 14 days until the patient has fulfilled these criteria. 
Day 1 Dose Missed 
If the dose held or missed was to be given on Day 1 of the next cycle, that next cycle 
will not be considered to start until the day the first dose is actually administered to the 
patient (ie, D1-D8-Rest, X-D1-D8-Rest, etc). 
Day 8 Dose Is Missed 
That week becomes the week of rest. Next dose (if counts and chemistries permit) 
becomes Day 1 of a new cycle (ie, D1-D8-Rest, D1-X, D1-D8-Rest, etc).   
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. 
Doses will be reduced for hematologic and other toxicities. Two levels of dose 
modifications are permitted according to the criteria below. Dose reductions will occur 


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sequentially (75 mg/m2 and 56 mg/m2), there should be no direct reduction by two dose 
levels. If a toxicity requiring dose modification occurs following the second dose 
reduction of ABI-009, further treatment should be discontinued. Dose adjustments are to 
be made according to the system showing the greatest degree of toxicity.  Toxicities will 
be graded using the NCI CTCAE Version 4.03. 
Guidelines for dose modifications and interruptions for management of common 
toxicities associated with the study treatment(s) are provided in this section: 
• General guidelines for clinically significant toxicities related to study treatment 
And 
• Specific guidelines for adverse events of special interest, which are events that 
have been observed with higher frequency or severity. 
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. Dose reduction of ABI-009 
should be considered as clinically indicated. 
 
If the toxicity does not resolve to at least grade 1 in less than 14 days, withdrawal from 
treatment with the IP is recommended. However, if the investigator and AADi Medical 
Monitor agree that further treatment would benefit the patient, treatment can continue 
with at least one dose level dose reduction, per Table 4.  
Table 4:  
Dose Level Reduction Guidelines 
Dose level 
ABI-009 Dose/Schedule 
0 
Initial Dose: 100 mg/m2 
-1 (first dose reduction) 
25% reduction of initial dose of 100: 75 mg/m2 
-2 (second dose reduction) 
25% reduction from 75 mg/m2: 56 mg/m2 
If an AE resolves to grade 1 or baseline at the reduced dose level, and no additional 
toxicities are seen during the following cycle of study treatment at the reduced dose, the 
dose may be increased to the previous dose level. 
Any patient meeting the criteria for Hy’s Law case (i.e. severe drug-induced liver injury) 
will be considered a dose-limiting toxicity. A Hy’s Law case is defined as: AST or ALT 
values of ≥ 3 x ULN AND with serum total bilirubin level (TBL) of > 2 x ULN without 
signs of cholestasis and with no other clear alternative reason to explain the observed 
liver-related laboratory abnormalities. 
ABI-009 dose modification guidelines are outlined in Table 4 and Table 5: for clinically 
significant toxicities that are deemed related. The dosing schedule is described in the 
Schedule of Assessments, Table 2. 


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Table 5:  Dose Modification Algorithms for Adverse Events Possibly Related to 
ABI-009 
 
System/Organ 
Adverse Event 
CTCAE 
Grade 
v4.03 
Dose modification Algorithm 
Mucosa 
Stomatitis, mucosal 
inflammation 
Grade 2 
Hold ABI-009 until resolution to Grade 
1 or baseline and restart at the same 
dose for 1st occurrence; for subsequent 
occurrences, drug will be restarted at a 
reduced dose; provide supportive care 
as clinically indicated. 
Grade ≥3 
Hold ABI-009 until resolution to Grade 
1 or baseline and restart at the same 
dose for 1st occurrence for subsequent 
occurrences, drug will be restarted at a 
reduced dose; provide supportive care 
as clinically indicated. 
Skin and 
Subcutaneous 
Tissue 
Disorders 
Skin rash 
Grade 2 
Tolerable: Continue ABI 009 at full 
dose, monitor as clinically indicated 
Intolerable: Hold ABI-009 until 
resolution to Grade 1 or baseline and 
restart at the same dose for 1st 
occurrence; for subsequent 
occurrences, drug will be restarted at a 
reduced dose; provide supportive care 
as clinically indicated. 
Grade ≥3 
Hold ABI-009 until resolution to Grade 
1 or baseline; for subsequent events, 
drug will be restarted at a reduced 
dose; provide supportive care as 
clinically indicated. 
Gastrointestinal 
Disorders 
Diarrhea despite 
optimal medication 
Grade 2 
Hold ABI-009 until resolution to Grade 
1 or baseline and restart at the same 
dose for 1st occurrences; for 2nd and 
subsequent events, drug will be 
restarted at a reduced dose; provide 
supportive care as clinically indicated. 
Grade ≥3 
Hold ABI-009 until resolution to Grade 
1 or baseline; for subsequent events, 
drug will be restarted at a reduced 
dose; provide supportive care as 
clinically indicated. 
Metabolic 
disorders 
Hyperlipemia 
(cholesterol, 
triglycerides) 
Grade 3 
If this is persistent for 2 months, 
reduce by 1 dose level at start of next 
cycle 


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Grade 4 
If this is persistent for 1 month, reduce 
by 1 dose level at start of next cycle 
Hyperglycemia 
Grades 1 
and 2 
Start at home 2x/day glucose 
monitoring; initiate medical 
management 
Grade 3 
Initiate medical management ; If 
recurrent post ABI-009 despite 
adequate medical management, 
reduce by 1 dose level 
Grade 4 
Initiate medical management, hold 
ABI-009 until grade 2 or less, restart 1 
dose level lower 
Hematologic 
toxicity 
Thrombocytopenia, 
Neutropenia, 
Anemia 
Grade 2 
ABI-009 can resume once meeting the 
following hematological requirements: 
ANC > 1.5 x 109/L, platelets > 100 x 
109/L and hemoglobin ≥9 g/dL 
Grade ≥3 
Hold ABI-009 immediately for the 
remainder of that cycle.  Repeat blood 
collection within 3 days.  ABI-009 can 
resume once meeting following 
requirements: absolute ANC >1.5 x 
109/L, platelet count > 100 x 109/L and 
hemoglobin ≥9 g/dL. For 2nd and 
subsequent events, drug will be 
restarted at a reduced dose; G-CSF 
may be given as deemed indicated. 
Respiratory 
events 
Pneumonitis, 
bronchiolitis 
obliterans, and/or 
organizing 
pneumonia 
Grade 2  
Hold ABI-009 immediately for up to 3 
weeks until resolved to ≤ grade 1, then 
reduce by 1 dose level. If it is still a 
Grade 2 after 3 weeks, discontinue 
treatment. If > Grade 2 recurs after 
resuming ABI-009 at a reduced dose 
level, discontinue treatment 
Grade ≥3 
Permanently remove patient from 
protocol treatment 
 
7.2.2. 
Hepatotoxicity Stopping Rules  
Patients with abnormal hepatic laboratory values (ie, ALP, AST, ALT, total bilirubin TBL) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis may meet 
the criteria for withholding or permanent discontinuation of ABI-009 as specified in the 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009. 


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7.2.2.1. 
Criteria for Permanent Discontinuation of ABI-009 Due to Potential 
Hepatotoxicity 
ABI-009 should be discontinued permanently and the patient should be followed for 
possible drug-induced liver injury (DILI), if ALL of the criteria below are met:  
• TBL > 2x upper limit of normal (ULN) or INR > 1.5x 
• AND increased AST or ALT from the relevant baseline value as specified 
below:  
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
≥ 3x ULN 
• AND no other cause for the combination of the above laboratory 
abnormalities is immediately apparent; important alternative causes for 
elevated AST/ALT and/or TBL values include, but are not limited to: 
− Hepatobiliary tract disease 
− Viral 
hepatitis 
(eg, 
Hepatitis 
A/B/C/D/E, 
Epstein-Barr 
Virus, 
Cytomegalovirus, Herpes Simplex Virus, Varicella, Toxoplasmosis, and 
Parvovirus) 
− Right sided heart failure, hypotension or any cause of hypoxia to the liver 
causing ischemia.   
− Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal 
and dietary supplements, plants and mushrooms   
− Heritable disorders causing impaired glucuronidation (eg, Gilbert’s 
Syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin 
glucuronidation (eg, indinavir, atazanavir) 
− Alpha-one antitrypsin deficiency 
− Alcoholic hepatitis 
− Autoimmune hepatitis  
− Wilson’s disease and hemochromatosis 
− Nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH)  
− Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
7.2.2.2. 
Criteria for Conditional Withholding of ABI-009 Due to Potential 
Hepatotoxicity 
For patients who do not meet the criteria for permanent discontinuation of ABI-009 and 
have no underlying liver disease, and eligibility criteria requiring normal transaminases 
and TBL at baseline or patients with underlying liver disease and baseline abnormal 
transaminases, the following rules are recommended for withholding of ABI-009: 
 
 


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• Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation  
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
> 5x ULN but < 8x ULN and unable to adhere to 
enhanced monitoring schedule 
Any 
≥ 3x ULN with clinical signs or symptoms that 
are consistent with hepatitis (such as right upper 
quadrant 
pain/tenderness, 
fever, 
nausea, 
vomiting, jaundice).   
• OR: TBL > 3x ULN at any time 
• OR: ALP > 8x ULN at any time 
ABI-009 should be withheld pending investigation into alternative causes of DILI.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, and ALP) and/or elevated TBL is discovered and the laboratory abnormalities 
resolve to normal or baseline. 
7.2.2.3. 
Criteria for Rechallenge with ABI-009 After Potential Hepatotoxicity 
The decision to rechallenge the patient should be discussed and agreed upon 
unanimously by the patient, investigator, and AADi medical monitor. 
If signs or symptoms recur with rechallenge, then ABI-009 should be permanently 
discontinued.  Patients who clearly meet the criteria for permanent discontinuation (as 
described in Section 7.2.1) should never be rechallenged. 
7.2.3. 
Overdose  
On a per dose basis, an overdose is defined as 10% over the protocol-specified dose 
of ABI-009 assigned to a given patient, regardless of any associated AEs or sequelae. 
On a schedule or frequency basis, an overdose is defined as anything more frequent 
than the protocol required schedule or frequency.  
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-
specified rate of 30 minutes for each infusion. 
 
 


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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 rapamycin and approximately 800 mg of 
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. 


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ABI-009 will be reconstituted by appropriate study personnel and administered to the 
patient in the study site (see below). The Investigator will calculate the BSA of the 
patient in order to determine the total amount of ABI-009 to be administered. 
Reconstitution and Use of ABI-009: 
1. Calculate the patient’s BSA according to standard institutional methods.  
BSA will be calculated at baseline and recalculated if the weight changes by >10%. 
 
Calculate the total dose (in mg) to be administered by:  
 
 
Total Dose (mg) = BSA × (study dose mg/m2) 
2. Calculate the total number of vials required by: 
 
 
Total Number of Vials = Total dose (mg) 
 
 
 
 
 
 
 
 
 
   100 (mg/vial) 
 
Round up the number of vials to be reconstituted to the next higher whole number 
when a fractional number of vials is obtained by the above formula (e.g., if the total 
number of vials = 4.05 or 4.5, then 5 vials would be reconstituted).  
3. Using sterile technique, prepare the vials for reconstitution. 
4. Swab the rubber stoppers with alcohol. 
5. Reconstitute each ABI-009 vial by using a 50-cc or 60-cc sterile syringe to inject  20 
mL of 0.9% Sodium Chloride Injection into each vial over a period of not less than 1 
minute (Note: Change the syringes after reconstituting every 3 vials).  
• Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride 
Injection. 
• Slowly inject the 20 mL of 0.9% Sodium Chloride Injection over a minimum of 1 
minute, using the sterile syringe to direct the solution flow onto the INSIDE 
WALL OF THE VIAL. 
• DO NOT INJECT the 0.9% Sodium Chloride Injection directly onto the lyophilized 
cake as this will result in foaming. 
• Once the injection is complete, allow the vial to sit for a minimum of 5 minutes 
to ensure proper wetting of the lyophilized cake/powder. 
• Gently swirl and/or invert the vial slowly for at least 2 minutes until complete 
dissolution of any cake/powder occurs. Avoid generation of foam. 
• If foaming or clumping occurs, stand solution for at least 15 minutes until foam 
subsides. 
• Each mL of reconstituted product will contain 5 mg of rapamycin. 
6. Calculate the exact total dosing volume (to the nearest mL) of 5 mg/mL suspension 
required for the patient: 
 
 
Dosing volume (mL) = Total dose (mg)/5 (mg/mL) 


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7. The reconstituted sample should be translucent and homogeneous without visible 
particulates. If unsuspended powder is visible, the vial should be gently inverted 
again to ensure complete resuspension, prior to use. 
8. Using a new, sterile 50-cc or 60-cc syringe, withdraw the reconstituted ABI-009 
solution. Do not remove the rubber stopper from the ABI-009 vials as this can 
compromise the sterility of the drug preparation. 
9. Inject the calculated dosing volume of reconstituted ABI-009 suspension into an 
empty sterile, standard PVC or non-PVC IV bag using an injection port. Inject 
perpendicularly into the center of the injection port to avoid dislodging plastic 
material into the IV bag. Repeat steps 9 and 10 until the patient’s entire required 
dose is injected into the IV bag. 
10. Remove the injection port. 
11. Once the exact volume of reconstituted ABI-009 has been withdrawn from the vials, 
discard any excess solution left over in accordance with standard operating 
procedures for cytotoxic drugs. 
12. Administer the calculated dosing volume of reconstituted ABI-009 suspension by IV 
infusion over 30 minutes (+/- 10 min). The use of in-line filters is not necessary; if 
used, in-line filters with pore sizes of < 15 microns (15 µm) should not be used. 
Upon completion of infusion, the infusion catheter should be flushed with ~2 mL 
normal saline to ensure all drug has been infused. 
13.  Reconstituted ABI-009 suspension in IV bag should be used immediately, but may 
be stored for up to 4 hours at 2-8°C (36°- 46°F), followed by 4 hours at room 
temperature (<25°C). 
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. 
• Rapamycin 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.  


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• 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.  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  


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1. 
Study Endpoints 
Primary Endpoint:  
• Objective Response Rate evaluated by independent review assessment 
Secondary Endpoint(s):  
• Duration of response  
• Progression-free survival rate at 6 months 
• Progression-free survival  
• Overall survival  
• Incidence and grade of treatment-emergent AEs 
Note: Analysis of secondary efficacy endpoints DOR, PFS rate at 6 months, median 
PFS, and median OS will be done separately for 2 subgroups of patients: 1) those with 
metastatic disease; and 2) those with locally advanced disease for which surgery is not 
an option. Patients in the locally advanced tumor subgroup may receive surgery if there 
is sufficient tumor shrinkage, which could introduce a bias in the assessment of the 
DOR, PFS rate at 6 months, median PFS, and OS. Safety will be analyzed in both 
patient groups together. 
Exploratory Endpoint(s): 
• Investigator assessed ORR 
• Pharmacokinetic/pharmacodynamic relationships for safety and/or efficacy 
endpoints  
• ABI-009 pharmacokinetic parameters including, but not limited to, maximum 
observed 
concentration 
(Cmax) 
of 
rapamycin, 
minimum 
observed 
concentration (Cmin), and area under the plasma concentration-time curve 
(AUC)  
• Presence/level of expression of several tumor biomarkers and their 
relationship to clinical responsiveness  
10.1.2. 
Analysis Sets 
Efficacy Analysis Set  
The Efficacy Analysis Dataset includes all enrolled patients with measurable tumor 
per RECIST v1.1 at baseline who receive at least one dose of ABI-009, and have a 
confirmed diagnosis of PEComa. The primary analysis of all efficacy endpoints will 
be performed on the Efficacy Analysis Dataset.   


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Full Analysis Set (Treated Population) 
The Full Analysis Set includes all enrolled patients who receive at least one dose of 
ABI-009.  All efficacy analyses will be repeated using the Full Analysis Data Set as 
sensitivity analyses. Analyses of safety endpoints will be performed on the Full 
Analysis set. 
Per-protocol Analysis Set  
The Per-protocol Analysis Set includes all enrolled patients who do not have any 
prospectively defined protocol violation. A sensitivity analysis of the primary and 
secondary efficacy endpoints may be performed on the PP Analysis Set. 
The relationship of the following covariates to efficacy endpoints will be explored if 
appropriate. 
10.1.3. 
Covariates and Subgroups 
Two groups of patients will be studied, those with metastatic disease and those with 
locally advanced disease for which surgery is not an option. The 2 subgroups of 
patients will be assessed together for the primary endpoint, ORR. However, 
because some of the patients in the locally advanced tumor subgroup may be clinically 
indicated to have surgery if there is sufficient tumor shrinkage, which would introduce a 
bias, the 2 groups will be analyzed separately for secondary endpoints, DOR, PFS rate 
at 6 months, PFS, and OS. 
In addition the following covariates may be used to examine efficacy and/or safety in 
subgroup or covariate analyses, if sufficient number of patients are enrolled in the 
subgroups: 
• Gender (male and female) 
• Age at enrollment (<65 vs ≥65 and <75 vs ≥75 years)  
• ECOG Performance Status at baseline (0 vs 1) 
• Time from initial diagnosis to enrollment 
10.2. 
Sample Size Considerations  
Sample size estimation is based on the primary efficacy endpoint, confirmed ORR: 
proportion of patients who achieve an objective response. 
A sample size of 30 patients will result in the half width of the 95% CI for the estimated 
ORR of no more than 18.7%.  Assuming an observed ORR of 30%, the lower bound of 
the 95% CI for the estimated ORR will exclude values less than 14.7%.  
10.3. 
Data Monitoring Committee (DMC) 
An external DMC will assess safety approximately when a third of patients are enrolled 
and have completed at least 2 cycles. On the basis of their review the DMC will make 
recommendations to AADi regarding the continuation of the study. The DMC will consist 
of at least 2 clinicians with relevant specialties and one statistician. Details regarding the 
responsibilities of the DMC will be outlined in the DMC charter.   


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10.4. 
Primary Analysis 
The objective of the primary analysis is to address all study objectives and it will be 
conducted when all patients have had the opportunity to be treated for at least 6 
months. All primary, secondary, and exploratory efficacy and safety analyses will be 
conducted at the time of the primary analysis, with the exception of the biomarkers 
which may be analyzed at a later date.     
The primary endpoint, ORR will be assessed by independent radiologic assessment. 
Overall response rate will also be evaluated by investigator assessment as an 
exploratory endpoint.  
10.5. 
Planned Methods of Analysis 
10.5.1. 
General Considerations 
A clinical study report will be generated for the primary analysis. The study report will be 
updated once the last data point is collected from the last patient that is required for 
primary, secondary, and/or exploratory analysis, as pre-specified in the protocol. 
The analyses of all study objectives will be descriptive and hypothesis generating in 
nature.   
Continuous variables will be summarized by the non-missing sample size (n), mean, 
standard deviation, first and third quartiles, minimum and maximum. Categorical 
variables will be summarized by the n and percent in each category.  
Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% 
exact binomial CI [69]. 
Time to event endpoints will be summarized descriptively using the KM method [70]. KM 
quartiles (when estimable) along with the 95% 2-sided CIs [71], the number of patients 
censored and the number of events will be provided. Kaplan Meier estimates will also 
be presented graphically.  
No adjustments for multiplicity are planned for the analysis of the efficacy endpoints.  
10.5.2. 
Primary Efficacy Endpoint 
The primary endpoint, ORR, will be determined by independent radiologist(s). The 
independent radiologic review will follow a separate imaging charter.  
The primary analysis will evaluate the independently assessed ORR in patients treated 
with ABI-009 by providing the number and proportion of patients achieving OR along 
with an exact binomial 95% CI for the proportion.  
Overall response rate is defined as the proportion of patients who achieve a confirmed 
PR or CR per RECIST 1.1. Patients without a post-baseline disease assessment will be 
considered not to have achieved a response. If an initial observation of objective 
response (CR or PR) is made, a confirmation scan should be done at 6 weeks after 
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The analysis of ORR will be conducted on the Efficacy Analysis Dataset. A sensitivity 
analysis will also be conducted using the Full Analysis Dataset. Analysis of ORR will 
include both subgroups of patients: 1) those with metastatic disease and 2) those with 
unresectable locally advanced disease or resectable with multiple resections.  
10.5.3. 
Secondary Efficacy Endpoints 
Analysis of secondary efficacy endpoints DOR, PFS rate at 6 months, median PFS, and 
median OS will be done separately for the 2 subgroups of: 1) those with metastatic 
disease; and 2) those with locally advanced disease for which surgery is not an option.  
The analysis of the DOR will be conducted on the Efficacy Analysis Dataset. A 
sensitivity analysis will also be conducted using the Full Analysis Dataset. For patients 
with metastatic disease the duration of response will be estimated by the KM method. 
The number of patients in the second subgroup:  those with locally advanced disease, is 
expected to be small. The DOR for these patients will be summarized descriptively by 
case reports.  
Only patients achieving an ORR will be included in the analysis of DOR. Duration of 
response is defined as the time from when criteria of response is first met until the first 
observation of disease progression per RECIST v 1.1 or death due to any cause, 
whichever comes first. Patients without any of these events will be censored at their last 
evaluable tumor assessment. 
The analysis of PFS rate at 6 months, PFS and OS will be conducted on the Efficacy 
Analysis Dataset. A sensitivity analysis will also be conducted using the Full Analysis 
Dataset. PFS rate at 6 months, median PFS, and OS for patients with metastatic 
disease will be summarized using KM methods.  
The number of patients in the second subgroup:  those with locally advanced disease, is 
expected to be small. The PFS rate at 6 months, PFS and OS for these patients will be 
summarized descriptively by case reports.  
Progression-free survival is defined as the time from the first dose date to the first 
observation of a disease progression or death due to any cause. If a patient has not 
progressed or died by the data cutoff date, the PFS time will be censored at the time of 
the last evaluable tumor assessment.  
Overall survival is defined as the time from the first dose date to the date of death due 
to any cause. If a patient is lost to follow-up before the data cutoff date or still alive by 
the data cutoff date the OS time will be censored at the last contact date.  
10.5.4. 
Safety Endpoints 
Safety (incidence and severity of adverse events and significant laboratory 
abnormalities) is a secondary endpoint. Safety analysis will be performed on all patients 
in the Full Analysis Set.  
Patient incidence of all treatment-emergent AEs will be tabulated by system organ class 
and preferred term. Tables of fatal adverse events, serious adverse events, treatment-
related AEs, and adverse events leading to withdrawal from investigation product will 


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also be provided. The MedDRA will be used to code adverse events and the NCI 
CTCAE version 4.03 will be used to grade severity of adverse events and laboratory 
toxicities. 
For ABI-009 exposure, summary statistic will be provided for total number of doses, 
average dose administered, and duration of treatment. 
For select laboratory parameters, changes of laboratory values over time (eg, change 
from baseline summary statistics), grade shifts in laboratory values from baseline to 
worst on-study value, and grade 3 or higher laboratory toxicities will be summarized.  
The ECG measurements from this study will be performed as per standard of care for 
routine safety monitoring.  
10.6. 
Pharmacokinetic Analysis 
Pharmacokinetic 
analysis 
will 
include 
all 
patients 
who 
received 
ABI-009. 
Pharmacokinetic analysis including but not limited to Cmax, AUC, Vd and Half-life will be 
performed at Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1 on total rapamycin in all 
patients who received ABI-009 as described in Section 6.5.  
 
 
 


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11. 
MONITORING, RECORDING AND REPORTING OF ADVERSE 
EVENTS  
11.1. 
Toxicities of ABI-009 
ABI-009 is a formulation of rapamycin. No unexpected toxicities not already known for 
rapamycin (Rapamune®) or the rapamycin 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 rapamycin and rapalogs 
are found in the Rapamune® and Torisel® Package Inserts [52, 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. Note: Disease progression and death 
due will not be recorded as an AE. 
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 appropriate CRF, see Section 7.2.3 for the definition of overdose. 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 


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dose of IP through the EOT Visit are reported using the applicable eCRF (eg, Adverse 
Event Summary CRF).  
11.2. 
Evaluation of Adverse Events  
The investigator must assign the following AE attributes: 
• 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.   


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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. 
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) 
• 
Disease progression 
• 
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. 


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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 regulatory mechanism. 


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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. 


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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. 
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 publically 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, tumor, 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.  
All samples and associated results will be no less than single coded prior to being 
shipped from the site for analysis, or storage. Tracking of samples will be independent 
of the patient’s identification number for the study. Results are stored in a secure 
database to ensure confidentiality.   


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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 
cancer, the dose response and/or prediction of response to ABI-009, characterize 
antibody response, 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 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, 
information, discoveries, or derivative materials gained or produced from the sample.  


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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, 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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