Conditions: Ewing Sarcoma PEComa Epithelioid Sarcoma Desmoid Tumor Chordoma Non Small Cell Lung Cancer Urothelial Carcinoma Melanoma Renal Cell Carcinoma Squamous Cell Carcinoma Hepatocellular Carcinoma Classical Hodgkin Lymphoma Colorectal Cancer MTOR Activating Mutation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
This study investigates the safety/toxicity and potential anti-tumor activity of sequential administration of nivolumab and escalating doses of the mammalian target of rapamycin (mTOR) inhibitor nab-rapamycin (ABI-009) in advanced Ewing's sarcoma, perivascular epithelioid cell tumor (PEComa), epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urothelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin's lymphoma, high microsatellite instability (MSI-H)/ mismatch repair deficient (dMMR) metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors.

Detailed description:
The primary objective of this study is to investigate the maximum tolerated dose (MTD) of ABI-009, an mTOR inhibitor, when given sequentially with nivolumab in advanced Ewing's sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urothelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin's lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors.

The secondary objectives are to investigate the disease control rate (DCR) and progression free survival (PFS) using nivolumab/ABI-009 combination therapy in advanced Ewing's sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urothelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin's lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors.

The exploratory objectives are (1) To correlate progression free survival (PFS) based on Immune-related Response Criteria (irRECIST) with that based on RECIST v1.1, and (2) To correlate PFS with programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) expression in patients' tumors.

Arms:
arm 1: This is an open label, dose-seeking phase 1b study using a defined dose of nivolumab and escalating doses of Nab-Rapamycin (ABI-009) given intravenously.

I. Dose Escalation Phase 1 Part of Study: The study will employ the standard "cohort of three" design. No intra-patient dose escalation will take place.

II. Expansion Phase 1b Part of Study: Following dose escalation, an additional 22-28 patients will receive ABI-009 at the MTD and defined doses of nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients in the expansion phase of the study may continue treatment up to 18 three-week cycles or until significant disease progression or unacceptable toxicity occurs.

Interventions: intervention 1: Nab-Rapamycin intervention 2: Nivolumab
Intervention descriptions: intervention 1: Escalating doses of ABI-009 will be given IV over 30 min for 2 of every 3 weeks beginning Day 8 Cycle 2. Only nivolumab will be given in Cycle 1. At Dose Level 1, 3-6 patients will receive 56 mg/m\^2; at Dose Level 2, 3-6 six patients will receive 75 mg/m\^2; and at Dose Level 3, 3-6 patients will receive 100 mg/m\^2. intervention 2: A defined dose of nivolumab, 3 mg/kg, will be given IV over 30 minutes q 3 weeks

Protocol document:
Prot_SAP_000.pdf: 
ABI-009/Nivolumab  
Protocol:SOC-1701                                             Sarcoma Oncology Research Center 
Confidential and Proprietary 
1 
Final Protocol: September 26, 2019 
ITLE PAGE 
 
A phase 1/2 investigation of safety/efficacy of nivolumab (Opdivo®) 
and ABI-009 (nab-rapamycin) in patients with advanced Ewing’s 
sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, 
non-small cell lung cancer, small cell lung cancer, urethelial 
carcinoma, melanoma, renal cell carcinoma, squamous cell 
carcinoma of head and neck, hepatocellular carcinoma, classical 
Hodgkin’s lymphoma, MSI-H/dMMR metastatic colorectal cancer, and 
tumors with genetic mutations sensitive to mTOR inhibitors 
 
INVESTIGATIONAL PRODUCT (IP): 
 
ABI-009; Nivolumab (Opdivo ®)  
PROTOCOL NUMBER: 
 
SOC-1701 
Version History: 
 
Vs 6.0 
Date: 
    
September 26, 2019   
 
 
 
IND NUMBER: 
 
 135985 
Cross Reference AADi IND NUMBER: 
 
125,669   
SPONSORS NAME/ ADDRESS: 
 
 
 
Collaborator: 
 
Sarcoma Oncology Research 
Center  
2811 Wilshire Blvd., Suite 414 
Santa Monica CA 90403 
 
AADi Bioscience, Inc 
1343 Luna Vista Dr 
Pacific Palisades, CA 90272 
 
 
 
 
CONFIDENTIAL: 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. 


ABI-009/Nivolumab  
Protocol:SOC-1701                                             Sarcoma Oncology Research Center 
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  PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
 
Signature of Site Principal Investigator 
 
dd mm yyyy 
 
Erlinda M. Gordon, MD 
Printed Name of Site Principal Investigator 
Institution Name:  Sarcoma Oncology Research Center   
By my signature, I agree to personally supervise the conduct of this study at my 
study site and to ensure its conduct is in compliance with the protocol, informed 
consent, Institutional Review Board (IRB)/Ethics Committee (EC) procedures, 
instructions from AADi representatives, the Declaration of Helsinki, ICH Good 
Clinical Practices Guidelines, and local regulations governing the conduct of 
clinical studies. 
 
 
 
Co-Investigators:   Doris Quon, MD 
 
 
 
 
 
 
 
Steven Wong, MD 
 
 
 
 
 
 
 
Ania Moradkhani, NP 
 
 
 
 
 
 
       
 
 
Study Coordinators: Victoria Chua-Alcala, Katherine Kim 
 
 
 
 
 
 
 
 
         
 
 
 
 
Sarcoma Oncology Research Center  
 
 
 
 
 
 
 
2811 Wilshire Blvd., Suite 414 
 
 
 
 
 
 
 
Santa Monica CA 90403 
 
 
 


ABI-009/Nivolumab  
Protocol:SOC-1701                                             Sarcoma Oncology Research Center 
Confidential and Proprietary 
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Final Protocol: September 26, 2019 
PROTOCOL SYNOPSIS 
Study Title 
A phase 1/2 investigation of safety/efficacy of nivolumab (Opdivo®) and ABI-009 (nab-
rapamycin) in patients with advanced Ewing’s sarcoma, PEComa, epithelioid sarcoma, 
desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, urethelial 
carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, 
hepatocellular carcinoma, classical Hodgkin’s lymphoma, MSI-H/dMMR metastatic 
colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors 
 
Study Number: SOC-1701 
 
Study Phase: 1/2 
 
Name of Investigational Product (IP) 
ABI-009, rapamycin protein-bound nanoparticles for injectable suspension (albumin 
bound), nab-rapamycin, nanoparticle albumin-bound rapamycin 
 
Name of FDA Approved Study Agent 
Nivolumab (Opdivo®), is a programmed death receptor-1 (PD-1) blocking monoclonal 
antibody indicated for the treatment of patients with (1) BRAF V600 wild-type 
unresectable or metastatic melanoma, as a single agent, (2) BRAF V600 mutation-
positive unresectable or metastatic melanoma, as a single agent. This indication is 
approved under accelerated approval based on progression free survival. (3) 
Unresectable or metastatic melanoma, in combination with ipilimumab, (4) Metastatic 
non-small cell lung cancer and progression on or after platinum-based chemotherapy, (5) 
Advanced renal cell carcinoma who have received prior anti-angiogenic therapy, (6) 
Classical Hodgkin lymphoma that has relapsed or progressed after autologous 
hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab 
vedotin, (7) Recurrent or metastatic squamous cell carcinoma of the head and neck with 
disease progression on or after a platinum-based therapy, and (8) advanced or metastatic 
urothelial carcinoma who have progressed on platinum-containing chemotherapy. 
 
Indication 
Previously treated patients with advanced (metastatic or locally advanced) sarcoma, 
including desmoid tumor and chordoma 
 
Objectives 
Primary Objective  


ABI-009/Nivolumab  
Protocol:SOC-1701                                             Sarcoma Oncology Research Center 
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Final Protocol: September 26, 2019 
The primary objective of this study is to investigate the maximum tolerated dose of ABI-
009, an mTOR inhibitor, when given sequentially with nivolumab in advanced UPS, LPS, 
OS, CS, Ewing’s sarcoma.  
 
Secondary Objectives  
The secondary objectives are to investigate the disease control rate (DCR), progression 
free survival (PFS), recurrence-free survival (RFS) and overall survival using 
nivolumab/ABI-009 combination therapy in advanced Ewing’s sarcoma, PEComa, 
epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung 
cancer, urethelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma 
of head and neck, hepatocellular carcinoma, classical Hodgkin’s lymphoma, MSI-
H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to 
mTOR inhibitors.  
 
Exploratory Objectives 
• To correlate disease control rate (DCR) based on Immune-related Response 
Criteria (irRECIST) with that based on RECIST v1.1. 
• To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors 
• To correlate DCR with PTEN mutation in patient’s archived tumor 
 
Endpoints 
Primary Endpoint 
• Maximum tolerated dose (MTD)  
Secondary endpoints 
• Disease control rate (DCR) as determined by a local radiologic assessment using 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; objective response 
rate (ORR; CR + PR), progression free survival (PFS), and overall survival (OS). 
• PFS rate at 3, 6, 9, and 12 months, RFS at 4 months, median PFS, median RFS 
and median OS will be assessed for all subtypes together, and separately in the 
five subtypes of patients with metastatic disease and locally advanced disease.   
Exploratory endpoints 
• Correlation between DCR based on Immune-related Response Criteria (irRECIST) 
with that based on RECIST v1.1. 
• Correlation between DCR and PD-L1 and other biomarker expression in patients’ 
tumors. 
• Correlation between DCR and PTEN mutation in patient’s archived tumor 


ABI-009/Nivolumab  
Protocol:SOC-1701                                             Sarcoma Oncology Research Center 
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Final Protocol: September 26, 2019 
 
Study Design 
This is an open label, dose-seeking phase 1/2 study using a defined dose of nivolumab 
and escalating doses of ABI-009 given intravenously.  
 
I. Dose Escalation Phase 1 Part of Study:  The study will employ the standard “cohort 
of three” design (2). Three patients are treated at each dose level with expansion to six 
patients per cohort if DLT is observed in one of the three initially-enrolled patients at each 
dose level. If no DLT occurs after 2 doses, escalation to the next dose level will be 
permitted. The maximum tolerated dose is defined as the highest safely tolerated dose, 
where not more than one patient experienced DLT, with the next higher dose level having 
at least two patients who experienced DLT. Patients in the dose escalation study may 
continue treatment at their designated dose levels up to eighteen 3-week cycles or until 
significant disease progression or unacceptable toxicity occurs. No intra-patient dose 
escalation will take place. 
 
Dose of nivolumab:  3 mg/kg IV over 30 min. q 3 weeks (Day 1 of every 21-day cycle) 
 
Dose of ABI-009:  
 
NB: ABI-009 will start after 2nd nivolumab dose and will be administered on D8 and D15 
beginning in C2. 
 
Escalating doses IV over 30 min for 2 of every 3 weeks: 
 
Treatment Cycle        # Pts.      Dose Level      Dose, mg/m2       
 
Every 3 weeks              3-6                   I                      56  
  
Every 3 weeks              3-6                  II                      75 
                      
Every 3 weeks              3-6                 III                    100  
 
Note: DLT includes any > Grade 3 colitis, hepatitis, or pneumonitis, any Grade 1-2 colitis, 
hepatitis or pneumonitis that recurs, worsens or persists with oral steroids longer than 14 
days, symptoms of adrenal crisis, any Grade 4 hematologic toxicity or any        > Grade 
3 non-hematologic toxicity. If DLT develops in more than 1 patient at Dose 56 mg/m2, the dose 
will be de-escalated to 45 mg/m2 and to 30 mg/m2 if DLT develops at 45 mg/m2. 
 
II. Expansion Phase 2 Part of Study: Following dose escalation, an additional 22-28 
patients will receive ABI-009 at the MTD and defined doses of nivolumab to assess overall 
safety and potential efficacy in a greater number of patients. Patients in the expansion 
phase of the study may continue treatment up to 18 3-week treatment cycles or until 
significant disease progression or unacceptable toxicity occurs. 
The study will be conducted in compliance with International Conference on 
Harmonisation (ICH) Good Clinical Practices (GCPs). 
Surgical Resection: After three or more treatment cycles, the principal investigator may 
recommend surgical debulking, complete surgical removal or a biopsy. If residual disease 


ABI-009/Nivolumab  
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is present either by histopathological examination or by CT scan/MRI, repeat treatment 
cycles may be given 2-4 weeks after surgery, if the surgical incision has healed, and if 
the patient has < grade I toxicity.  
 
Resected or biopsied tumors will be analyzed for the effects of this dual therapy on 
disease control rate, and immune cell trafficking in the tumor microenvironment. Fresh 
and paraffin embedded tissue blocks will be analyzed by FACS for PD-L1 and other 
biomarkers, including Tregs, CD8+, CD4+ cells etc. Immunohistochemistry for cyclin G1, 
cyclin D1 and Ki67 will be conducted to determine the tumor's proliferative state. 
Histopathologic examination for tumor necrosis and mitotic index will also be determined. 
 
Conditions for Continuation of Treatment in the Presence of Increased Tumor 
Size by CT scan or MRI Indicating Progressive Disease by RECIST v1.1: 
Treatment may be continued if: 
1. There are no signs or symptoms indicating unequivocal progression. 
2. There is no worsening of ECOG score attributable to progressive disease. 
3. There is no tumor growth at critical sites that is life-threatening. 
4. Patient signs an informed consent that he/she is aware of alternative therapies but 
wishes to defer these therapies. 
5. There is clinical benefit, as determined by investigator 
 
Sample Size 
40-50 patients may be enrolled. Patients who fail to become evaluable for the secondary 
endpoint with a follow-up CT/MRI will be replaced.  
 
Study Population 
Histology of Ewing’s sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, 
non-small cell lung cancer, small cell lung cancer, urethelial carcinoma, melanoma, renal 
cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, 
classical Hodgkin’s lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors 
with genetic mutations sensitive to mTOR inhibitors, will be confirmed locally by the 
institution prior to enrollment. 
 
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 Ewing’s sarcoma, 
PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung 
cancer, small cell lung cancer, urethelial carcinoma, melanoma, renal cell 


ABI-009/Nivolumab  
Protocol:SOC-1701                                             Sarcoma Oncology Research Center 
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Final Protocol: September 26, 2019 
carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, 
classical Hodgkin’s lymphoma, MSI-H/dMMR metastatic colorectal cancer, and 
tumors with genetic mutations sensitive to mTOR inhibitors, that is either 
metastatic or locally advanced and for which surgery is not a recommended option. 
2. Patients must have one or more measurable target lesions by CT scan or MRI. 
Measurable disease by RECIST v1.1, confirmed by investigator 
3. Previously treated patients with Ewing’s sarcoma, PEComa, epithelioid sarcoma, 
desmoid tumor, chordoma, non-small cell lung cancer, small cell lung cancer, 
urethelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma 
of head and neck, hepatocellular carcinoma, classical Hodgkin’s lymphoma, MSI-
H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive 
to mTOR inhibitors, if treatment is completed after 5 half-lives or ≥28 days prior to 
enrollment, whichever is shorter. 
4. Eligible patients, 12-17 years (>40 kg) or 18 years or older, with Eastern 
Cooperative Oncology Group (ECOG) performance status 0 or 1. 
5. 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/ALT ≤2.5 x ULN (≤5 x ULN if attributable to liver metastases); alk     
phos < 3 x ULN (patients with alk phos >3ULN will be allowed if due to bone 
metastases) 
c. Serum creatinine ≤1.5 x ULN 
6. 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.  
7. Serum triglyceride <300 mg/dL; serum cholesterol < 350 mg/dL. 
8.  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 


ABI-009/Nivolumab  
Protocol:SOC-1701                                             Sarcoma Oncology Research Center 
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participating in the study. A second form of birth control is required even if he 
has undergone a successful vasectomy. 
9.  Life expectancy of >3 months, as determined by the investigator. 
10.  Ability to understand and sign informed consent. 
11.  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. 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. 
2. Active gastrointestinal bleeding. 
3. Pre-existing thyroid abnormality is allowed provided thyroid function can be 
controlled with medication. 
4. 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). 
5. 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. 
6. 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). 
7. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate 
therapy. 
8. Unstable coronary artery disease or myocardial infarction during preceding 6 
months. 
9. Receiving any concomitant antitumor therapy. 


ABI-009/Nivolumab  
Protocol:SOC-1701                                             Sarcoma Oncology Research Center 
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Final Protocol: September 26, 2019 
10. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary 
hypertension. 
11. 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.  
12. Active Hepatitis B or Hepatitis C.  
13. Non-oncology vaccine therapy used for prevention of infectious disease within 4 
weeks of trial enrollment 
14. Autoimmune disease including rheumatoid arthritis, systemic progressive 
sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis 
and motor neuropathy considered to be of autoimmune origin (e.g. Guillain-Barre 
Syndrome) 
15. Systemic immunosuppression, including HIV positive status with or without AIDS 
16. Skin rash (psoriasis, eczema) affecting > 25% body surface area 
17. Inflammatory bowel disease (Crohn’s or ulcerative colitis) 
18. Ongoing or uncontrolled diarrhea within 4 weeks of trial enrollment 
19. Recent history of acute diverticulitis, intraabdominal abscess or gastrointestinal 
obstruction within 6 months of trial enrollment, which are known risk factors for 
bowel perforation  
20. Current, active or previous history of heavy alcohol abuse  
21. Pituitary endocrinopathy 
22. Adrenal insufficiency or excess 
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 or 
nivolumab. 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 or nivolumab.   
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. 


ABI-009/Nivolumab  
Protocol:SOC-1701                                             Sarcoma Oncology Research Center 
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Study Treatment 
Patients will receive nivolumab 3 mg/kg as IV infusion over 30 min every 3 weeks (Day 1 
of every 21-day cycle), followed by escalating doses of ABI-009 30, 45, 75 mg/m2 for 2 of 
every 3 weeks by IV infusion over 30 minutes. ABI-009 dosing will start after 2nd 
nivolumab dose and to be administered on Day 8 and Day 15 of every cycle beginning in 
Cycle 2. Patients will continue therapy until unequivocal clinical disease progression, 
unacceptable toxicity, or until in the opinion of the investigator the patient is no longer 
benefiting from therapy, or at the patient’s discretion. 
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 signs, laboratory assessments (e.g., serum chemistry, 
hematology), and ECOG performance status will be monitored. All SAEs (regardless of 
relationship to IP) will be followed until resolution. Local laboratory analysis will be 
performed as per study schedule.  
The MTD for ABI-009 will be determined, and will be used in the Phase 2 part of the study. 
Overview of Key Efficacy Assessments 
Patients will be evaluated for disease control rate [complete response (CR), partial 
response (PR), and 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 the end 
of treatment. 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 efficacy endpoints, DCR (CR, PR and SD), OR (CR + PR), PFS, and RFS will be 
determined by a local radiologic assessment using RECIST v1.1. After end of treatment, 
patients will be followed for survival every 12 weeks (+/- 3 weeks), or more frequently as 
needed, until death, withdrawal of consent, or the study closes, whichever is the earliest.  
 
Statistical Considerations 
Safety Analyses: 


ABI-009/Nivolumab  
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Demographic and baseline information (e.g., extent of prior therapy) on study patients 
will be tabulated. The number of patients studied for the Phase 1 (dose escalation) part 
of study could range from 12 to 18 evaluable patients, and 22-28 evaluable patients for 
the Phase 2 (dose expansion) part of the study.   
For the Phase 1 part of the study, the following information will be reported for all 
adverse events observed in the study: dose level, type (organ affected or laboratory 
determination, such as absolute neutrophil count), severity (by NCI Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 and most extreme 
abnormal values for laboratory determinations) and relatedness to study treatment.  For 
each dose the number and percentage of patients experiencing any grade 3, 4, or 5 
adverse event will be reported, as well as the number and percentage of patients who 
experienced selected specific types of adverse events.  In addition, the DLTs will be 
summarized by dose level and the MTD will be determined. 
The following table gives the probability of dose escalation at a single dose level as a 
function of the true probability of DLT at that level using the cohorts of 3 design 
(Objective #1) (2).    
 
 
 
 
 
Table 1.  
Probability of Dose Escalation 
True Rate of DLT (%) 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 
30 
0.49 
40 
0.31 
50 
0.17 
For the Phase 1 part of the study, the entire treated population (Full Analysis Set) will be 
the analysis population for all safety analyses. Adverse events will be coded using the 
NIH CTCAE v4.03. 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 all 
patient groups together (metastatic and locally advanced). Although this study will not 
be large enough to allow firm conclusions about safety or efficacy, it will provide 
preliminary data on safety and efficacy that will be useful in planning future studies. 
Frequency tables, graphs, and summary statistics will be used for outcome data.  
Patient incidence of all treatment-emergent AEs will be tabulated. Tables of fatal adverse 
events, serious adverse events, treatment-related AEs, and adverse events leading to 
withdrawal from investigation product will also be provided.  
For ABI-009 and nivolumab exposure, summary statistics will be provided for total number 
of doses, average dose administered, and duration of each treatment. 
Efficacy Analyses: 


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The disease control rate (DCR; CR+PR+SD), objective response rate (ORR; CR + PR), 
progression free survival (PFS), and recurrence-free survival (RFS) will be assessed by 
a local radiologic assessment using Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 and irRECIST. 
The focus of the study is to estimate the DCR in patients treated with ABI-009 and 
nivolumab. Patients who progress before receiving ABI-009 will be replaced, and will not 
be included in the statistical analysis. The number and percentage of patients achieving 
response will be summarized.   
Analysis of other efficacy endpoints, PFS at 4 months, RFS at 4 months, median PFS, 
and median OS will be assessed for all subtypes together, and separately in the five 
sarcoma subtypes.  
PFS, RFS and OS will be summarized using Kaplan-Meier (KM) analysis. The number of 
patients in each category is expected to be small; therefore, PFS at 4 months, RFS at 4 
months, median PFS, median RFS and median OS for these patients will be summarized 
by descriptive statistics. 
 
Exploratory Analysis: 
DCR based on RECIST v1,1 will be correlated with DCR based on Immune-related 
Response Criteria (irRECIST) and summarized by descriptive statistics. 
PD-L1 and other biomarker expression in patients’ tumors will be correlated with DCR 
PFS, and RFS and summarized by descriptive statistics. 
DCR will be correlated with presence of PTEN mutation in patient’s archived tumor and 
summarized by descriptive statistics.


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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................... 1 
PROTOCOL SYNOPSIS ................................................................................................. 3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................... 18 
1. 
INTRODUCTION .......................................................................................... 22 
1.1. 
Soft Tissue Sarcoma .................................................................................... 22 
1.2. 
ABI-009 Background .................................................................................... 26 
1.2.1. 
Rapamycin and Rapalogs ............................................................................ 26 
1.2.2. 
ABI-009 (nab-Rapamycin) ............................................................................ 27 
1.2.3. 
Preclinical Studies with ABI-009................................................................... 28 
1.2.4. 
Clinical Studies with ABI-009 ....................................................................... 29 
1.3. 
Nivolumab Background ................................................................................ 29 
1.3.1. 
Nivolumab Mechanism of Action .................................................................. 30 
1.3.2. 
Nivolumab Clinical Studies ........................................................................... 30 
1.3.3. 
Nivolumab Adverse Events .......................................................................... 31 
1.4. 
Rationale for the Schedule of the Study ....................................................... 34 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................... 35 
2.1. 
Objectives .................................................................................................... 35 
2.1.1. 
Primary Objectives ....................................................................................... 35 
2.1.2. 
Secondary Objectives .................................................................................. 35 
2.1.3. 
Exploratory Objectives ................................................................................. 35 
2.2. 
Endpoints ..................................................................................................... 35 
2.2.1. 
Primary Endpoint .......................................................................................... 35 
2.2.2. 
Secondary Endpoints ................................................................................... 35 
2.2.3. 
Exploratory Endpoints .................................................................................. 36 
2.3. 
Study Design ................................................................................................ 36 
2.4. 
Study Duration ............................................................................................. 37 
2.5. 
End of Study, End of Treatment, End of Treatment Visit, Follow-up 
Period ........................................................................................................... 38 
3. 
STUDY POPULATION ................................................................................. 39 
3.1. 
Number of Patients ...................................................................................... 39 
3.2. 
Inclusion Criteria .......................................................................................... 39 
3.3. 
Exclusion Criteria ......................................................................................... 40 


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4. 
TABLE OF EVENTS .................................................................................... 42 
5. 
PROCEDURES ............................................................................................ 45 
5.1. 
Screening Evaluations ................................................................................. 45 
5.2. 
Treatment Period ......................................................................................... 46 
5.2.1. 
Day 1 Assessment ....................................................................................... 46 
5.2.2. 
Day 8 Assessment ....................................................................................... 47 
5.2.3. 
Day 15 Assessment ..................................................................................... 47 
5.2.4. 
Response Assessment ................................................................................ 47 
5.3. 
End of Treatment Visit Assessment ............................................................. 48 
5.4. 
Follow-up Period for Survival and Initiation of Anticancer Therapy .............. 49 
6. 
DESCRIPTION OF STUDY TREATMENTS (ABI-009/NIVO) ...................... 50 
6.1. 
ABI-009/Nivolumab Dosage, Administration, and Schedule ......................... 50 
6.2. 
ABI-009 Dose Modification and Stopping Rules .......................................... 50 
6.2.1. 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation .......................................................................... 50 
6.2.2. 
Hepatotoxicity Stopping Rules ..................................................................... 53 
6.2.2.1. 
Criteria for Permanent Discontinuation of ABI-009 Due to Potential 
Hepatotoxicity............................................................................................... 54 
6.2.2.2. 
Criteria for Conditional Withholding of ABI-009 Due to Potential 
Hepatotoxicity............................................................................................... 54 
6.2.2.3. 
Criteria for Rechallenge with ABI-009 After Potential Hepatotoxicity ........... 55 
6.2.3. 
Overdose ..................................................................................................... 55 
6.3. 
Nivolumab Dose Modification and Stopping Rules ....................................... 56 
6.3.1. 
Dose Modification and Stopping Rules ........................................................ 56 
6.3.2. 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation .......................................................................... 57 
7. 
STUDY DRUG MANAGEMENT ................................................................... 58 
7.1. 
Description of Study Drugs .......................................................................... 58 
7.1.1. 
ABI-009 Packaging, Labeling, and Storage ................................................. 58 
7.1.2. 
Nivolumab Packaging, Labeling and Storage .............................................. 58 
7.2. 
ABI-009 and Nivolumab Accountability, Disposal, and Compliance ............. 58 
7.3. 
ABI-009 Reconstitution ................................................................................ 59 
7.4. 
Receipt and Return of ABI-009 .................................................................... 61 
7.5. 
Nivolumab (Opdivo) Reconstitution .............................................................. 61 


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7.6. 
Concomitant Medications and Procedures ................................................... 62 
7.7. 
Permitted Medications and Procedures ....................................................... 62 
7.8. 
Prohibited Medications and Procedures ....................................................... 62 
8. 
STATISTICAL CONSIDERATIONS ............................................................. 64 
8.1. 
Study Endpoints ........................................................................................... 64 
8.2. 
Safety Analysis............................................................................................. 64 
8.3. 
Efficacy Analysis .......................................................................................... 65 
8.4. 
Exploratory Analysis ..................................................................................... 66 
8.5. 
Covariates and Subgroups ........................................................................... 66 
8.6. 
Sample Size Considerations ........................................................................ 67 
8.7. 
Primary Analysis .......................................................................................... 67 
8.8. 
Planned Methods of Analysis ....................................................................... 67 
8.8.1. 
General Considerations ............................................................................... 67 
8.8.2. 
General Considerations ............................................................................... 67 
8.8.3. 
Other Secondary Efficacy Endpoints ............................................................ 68 
9. 
MONITORING, RECORDING AND REPORTING OF ADVERSE 
EVENTS ....................................................................................................... 69 
9.1. 
Toxicities of ABI-009 .................................................................................... 69 
9.2. 
Toxicities of Nivolumab ................................................................................ 69 
9.3. 
Evaluation of Adverse Events ...................................................................... 70 
9.4. 
Serious Adverse Events ............................................................................... 70 
9.4.1. 
Definition of Serious Adverse Events ........................................................... 70 
9.4.2. 
Reporting Procedures for Serious Adverse Events ...................................... 71 
9.5. 
Pregnancy and Breast Feeding Reporting ................................................... 71 
10. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY ........ 72 
10.1. 
Discontinuation from Investigational Product ............................................... 72 
10.2. 
Discontinuation from the Study .................................................................... 72 
10.3. 
Investigator or Sponsor Decision to Withdraw or Terminate Patient’s 
Participation Prior to Study Completion ........................................................ 72 
11. 
REGULATORY OBLIGATIONS ................................................................... 74 
11.1. 
Informed Consent ......................................................................................... 74 
11.2. 
Institutional Review Board/Independent Ethics Committee .......................... 74 
11.3. 
Patient Confidentiality .................................................................................. 75 


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11.4. 
Protocol Amendments .................................................................................. 75 
11.5. 
Termination of the Study .............................................................................. 75 
12. 
DATA HANDLING AND RECORDKEEPING ............................................... 76 
12.1. 
Data/Documents .......................................................................................... 76 
12.2. 
Data Management ........................................................................................ 76 
12.3. 
Investigator Responsibilities for Data Collection .......................................... 76 
12.4. 
Sample Storage and Destruction ................................................................. 77 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................... 79 
13.1. 
Study Monitoring .......................................................................................... 79 
13.2. 
Audits and Inspections ................................................................................. 79 
14. 
PUBLICATIONS ........................................................................................... 80 
15. 
REFERENCES............................................................................................. 81 
16.  
 
APPENDIX: Adverse Event Management Algorithms for Nivolumab………..84 
 
 
 


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LIST OF TABLES 
Table 1.  Probability of Dose Escalation ..................................................................... 11 
Table 2.  Schedule of Assessments ............................................................................ 43 
Table 3.  Analyte Listing .............................................................................................. 48 
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 ...................................... 28 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine transaminase (SGPT) 
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 
CI 
confidence interval 
CNS 
central nervous system 
CR 
CS 
complete response 
chondrosarcoma 
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 
CRF 
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 
LPS 
Immunohistochemistry 
liposarcoma 
 


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IND 
investigational new drug  
IP 
investigational product 
IRB 
Institutional Review Board 
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 
OS 
overall response rate 
osteosarcoma 
OS 
DCR 
overall survival 
disease control rate 
PD 
progressive disease 
PEComa 
perivascular epithelioid cell tumors  
PFS 
RFS 
Progression-free survival 
Recurrence-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) 
TBL 
total bilirubin level 
ULN 
UPS 
upper limit of normal 
undifferentiated pleomorphic sarcoma 
 
 


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Abbreviation or Term 
Definition/Explanation 
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 or nivolumab which ever 
is later 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 or nivolumab 
whichever is later.  
Primary Analysis 
 
For this study will occur after all patients have either completed 
the study or completed 12 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 received at least two doses of ABI-009 and had 
a follow-up CT scan/MRI (modified treated population) 
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.  


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Progression-free 
survival 
The time from the first dose date to the first observation of a 
disease progression or death due to any cause.   
Recurrence-free 
survival 
The time from the first dose date to the first observation of 
disease progression or recurrence/progression after surgical 
resection, 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 a local radiologic assessment   
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. 
Soft Tissue Sarcoma  
Soft tissue sarcoma (STS) is a relatively rare neoplasm of mesenchymal origin, which 
includes a diversity of histological subtypes and occurs with an incidence of about 1% of 
all adult cancers.  Surgical resection is still the treatment of choice for localized disease, 
along with radiation therapy for unresectable sarcomas. However, recurrence rate is high 
(~50%) and treatment options for metastatic/relapsed STS are limited to anthracycline-
based chemotherapy (i.e., doxorubicin), administered alone or in combination with 
alkylating agents (ifosfamide and/or dacarbazine) (3, 4). Judging from studies conducted 
over the last 20 years, prognosis for advanced STS has been uniformly poor, with an 
estimated median survival of only 8 to 13 months (5-7). Recently, two new drugs for soft 
tissue sarcoma have been approved by the United States Food and Drug Administration 
(USFDA). The first drug, pazopanib (Votrient®, Novartis Pharma), is a multiple tyrosine 
kinase inhibitor, which hinders growth factor-mediated signal transduction pathways 
involved in tumor angiogenesis (8-10). The second drug, trabectedin/ET-743 (Yondelis®, 
Janssen Biotech, Inc.), is a natural alkaloid, originally isolated from the Caribbean 
tunicate, Ecteinascidia turbinata, which interacts with DNA in a complex manner that 
interferes with gene transcription and DNA repair (11). Following the approval of 
trabectedin in Europe for treatment-resistant STS (12, 13) and the results of a pivotal 
Phase 3 trial (14), which enabled its approval in the United States for liposarcoma and 
leiomyosarcoma in 2015, there is renewed optimism for improving the quality of life, 
progression-free survival, and potentially, the overall survival of advanced STS patients 
that have failed standard therapies (14, 15).  
1.1.1 mTOR Inhibitors in Soft Tissue Sarcoma 
Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and 
other malignancies. Drug resistance and toxicities often limit beneﬁts of systemic 
chemotherapy used to treat metastatic sarcomas. Ridaforolimus is an inhibitor of 
mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT 
signaling pathway, with early evidence of activity in sarcomas.  
A multicenter, open-label, single-arm, phase II trial was conducted to assess the 
antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas 
(Chawla et al. A total of 212 patients were treated in four separate histologic cohorts. In 
this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 
15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors 
(RECIST) conﬁrmed response rate was 1.9%, with four patients achieving conﬁrmed PR 
(two with osteosarcoma, one with spindle cell sarcoma, and one with undifferentiated 
pleomorphic sarcoma [formerly malignant ﬁbrous histiocytoma]). Archival tumor protein 
markers analyzed were not correlated with CBR. Related adverse events were generally 
mild or moderate and consisted primarily of stomatitis, mucosal inﬂammation, mouth 
ulceration, rash, and fatigue. Conclusion: Single-agent ridaforolimus in patients with 
advanced and pretreated sarcomas led to PFS results that compare favorably with 
historical metrics.  


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A large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor 
ridaforolimus to assess maintenance of disease control in advanced sarcomas after 
benefit from prior chemotherapy (16). Patients with metastatic soft tissue or bone 
sarcomas who achieved objective response or stable disease with prior chemotherapy 
were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 
days every week. Primary end point was progression-free survival (PFS); secondary end 
points included overall survival (OS), best target lesion response, safety, and tolerability. 
A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus 
treatment led to a modest, although signiﬁcant, improvement in PFS per independent 
review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P < .001; 
median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target 
lesion size versus a 10.3%increase with placebo (P < .001). Median OS with ridaforolimus 
was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = 
.46). Adverse events (AEs) more common with ridaforolimus included stomatitis, 
infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and 
rash. Grade 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). 
Conclusion: Ridaforolimus delayed tumor progression to a small statistically signiﬁcant 
degree in patients with metastatic sarcoma who experienced beneﬁt with prior 
chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR 
inhibition. These data provide a foundation on which to further improve control of 
sarcomas. 
Other mTOR inhibitors, including sirolimus and everolimus, have been tested or are being 
tested in clinical trials for advanced soft tissue sarcoma. For example, sirolimus, is 
currently approved for immunosuppression following organ transplantation. However, 
there is increasing interest in its role as a neoplastic agent. In a report of four cases of 
progressive metastatic sarcoma in patients who have progressed after 2–6 lines of 
chemotherapy, treatment with sirolimus resulted in minor radiographic improvement in 
three cases (17). Myxoid chondrosarcoma has also been reported to respond well to 
sirolimus in combination with cyclophosphamide (18). 
Further, a phase II study investigating the efficacy of everolimus in patients with 
histological evidence of progressive or metastatic bone or soft tissue sarcoma is 
currently underway (19), as is a phase I/II study of everolimus in pediatric patients with 
recurrent or refractory solid tumors (20). 
1.1.2 Immune Checkpoint Inhibitors in Soft Tissue Sarcoma 
Immune check point inhibitors have become a mainstay of therapy for melanoma and are 
currently being developed for various solid tumors including renal cell carcinoma, non-
small cell lung cancer, ovarian cancer, head and neck cancer and lymphoma. The 
underlying principle is to thwart the defenses (checkpoints) that tumors utilize to cripple 
the immune system. Examples of FDA-approved immune checkpoint inhibitors include 
monoclonal antibodies ipilimumab and nivolumab (21). Ipilimumab (Yervoy®) is a 
recombinant human IgG1 monoclonal antibody that blocks the human cytotoxic T-
lymphocyte antigen (CTLA-4) which tumors use to overturn the immune system. CTL4 is 
one of several co-inhibitory molecules that help in controlling the T-cell response to 
stimuli/cancer cells. Cancer cells bind to the CTL-4 antigen to avoid the destruction by 


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cytotoxic T cells. In a pivotal phase III study, ipilimumab in combination with a glycoprotein 
100 (gp100) peptide vaccine improved overall survival in Stage III or IV unresectable 
melanoma. These results, together with two other supportive studies, formed the basis of 
FDA approval for unresectable or metastatic melanoma (22, 23). Nivolumab (Opdivo®) 
is a human IgG4 monoclonal antibody that blocks the programmed death receptor-1 (PD-
1). It is indicated for the treatment of patients with unresectable or metastatic melanoma 
and disease progression following ipilimumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor. This indication is approved under accelerated approval by the USFDA 
(23). 
Recently, the results of a multicenter phase 2 study (SARC028) investigating the safety 
and efficacy of pembrolizumab, a programmed death -1 (PD-1) inhibitor, in advanced soft 
tissue sarcoma and bone sarcoma (SARC028) showed that the ORR in the overall STS 
cohort was 18% and the 12-wk PFS 55% [95% CI, 42-71]). Clinical activity was variable 
by histologic subtype with 40% ORR in UPS (1 CR and 3PR out of 10 evaluable pts), 2 
PR/10 were seen in DDLPS, 1PR/10 in SS and 0/10 in LMS. For BS, median follow-up 
was 12.3 months (ORR 5%; 12-wk PFS 28% [95% CI, 14-41]), with 1PR/22 OS, 1PR/5 
CS and 0/13 ES. Seventy pre-pembrolizumab tissues were analyzed with PD-L1+ in 3/70 
(4%); all 3 were UPS. Of the 2 evaluable pts, 1 had CR and 1 PR. Two OS were PD-L1+ 
on multi-color IHC, 1 had PR. All PD-L1+ samples had CD8+ T-cell infiltration. There were 
no post-pembro PD-L1+ samples. The authors concluded that pembrolizumab has clinical 
activity in UPS and LPS, and expansion cohorts in those subtypes are planned. Pre-
treatment PD-L1 expression was infrequent, but correlated with T-cell infiltration and 
response in UPS & OS (24).  
1.1.3 Combination Chemo-/Immuno- therapy for Soft Tissue Sarcoma 
Understanding the bifunctional role that the immune system plays in tumor eradication vs 
growth promotion is critical in the design and timing of combination tumoricidal and 
immunologic therapies for sarcomas (25). Hence, immune checkpoint inhibitors that 
promote sustained T cell activation by suppressing T regs, may have synergistic activity 
with a tumoricidal agent, such as ABI-009, an mTOR inhibitor, whose plausible 
mechanism of action is to destroy the cancer cells and expose the tumor neoantigens for 
immune recognition. 
The initial results of our study on the feasibility of sequential administration of trabectedin 
and nivolumab support this concept. Trabectedin has direct cytotoxic activity in tumor 
cells and has also been shown to deplete pro-tumor macrophages in the tumor 
microenvironment (26). Nivolumab inhibits the immune checkpoint molecule, PD-1, which 
restores anti-tumor activity in tumor-infiltrating T cells. The objectives were to assess the 
safety/toxicity and efficacy of sequential administration of trabectedin and nivolumab in 
patients with advanced soft tissue sarcoma (STS). Fourteen patients with locally-
advanced and/or metastatic STS were evaluated. Each patient received 1 dose of single-
agent trabectedin (1.5 mg/kg continuous intravenous infusion, CIV, for 24 hours), followed 
by sequential administration of trabectedin CIV and nivolumab (3 mg/kg IV over 30 
minutes) every 3-4 weeks, starting 3 weeks after the first trabectedin dose. 
Dexamethasone (6-20 mg IV over 30 minutes) was given prior to each trabectedin 
treatment. Safety/toxicity was analyzed using the NIH/NCI CTCAE v.4.03. Baseline and 


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follow-up CT scans or MRIs were performed after every 2 cycles of the sequential chemo-
/immuno-therapy. Tumor responses were assessed by RECIST v1.1 and immune-related 
response criteria (irRC). Histologic subtypes include malignant fibrous histiocytoma / 
undifferentiated pleomorphic sarcoma (n = 6), leiomyosarcoma (n = 3), synovial sarcoma 
(n = 2), myxoid liposarcoma (n = 2) and chondrosarcoma (n = 1). All patients had 
metastatic disease and a median of 4 lines of prior chemotherapy.  Safety analysis: Grade 
3 treatment emergent adverse events include anemia (n=1), fatigue (n = 1), decreased 
platelet count (n=1), and increased creatine kinase (n=1). These AEs have been reported 
with trabectedin use. No immune-related adverse event has been observed so far. 
Efficacy analysis: Thirteen patients received 2 cycles of sequential chemo-/immuno-
therapy, had follow-up CT scan or MRI, and were evaluated for objective response (OR), 
best overall response rate, (BORR), disease control rate (DCR), progression-free survival 
(PFS) and overall survival (OS). There were 2 partial responses (PR), with one biopsied 
nodule showing >90% liquefaction necrosis, 8 stable disease (SD) and 3 progressive 
disease (PD), with best overall response rate (BORR) of 15.3%, DCR of 76.9%, median 
PFS of >8 weeks (range: 8-21 weeks), and median OS of >8 weeks (12.3->21 weeks). 
To our knowledge, this study is the first to explore sequentially administered chemo-
/immuno-therapy in patients with advanced STS.  The initial data suggest that paired 
administration of trabectedin and nivolumab is safe. We continue to evaluate for safety 
as well as synergistic activity based on their mechanisms of action on the tumor-immune 
microenvironment (27).  
 
1.1.4  
Strategies to improve the efficacy of immune checkpoint inhibitors in 
other clinical indications. 
Recently, several studies focused in modifying the tumor-immune microenvironment 
(TME) with small molecules that increase the number of activated T cells exerting 
tumoricidal activity and/or suppressing growth promoting macrophages in the TME. 
These drugs include microbiota modifiers, drugs targeting co-inhibitory receptors, anti-
angiogenic therapeutics, small molecules, and oncolytic viruses.  
The vascular network with its specific components (endothelial cells, pericytes, growth 
factors, and receptors) plays a key role in the regulation of inflammatory response, wound 
healing, and immune surveillance. The transit of immune cells in the tumor plays a critical 
role in the outcome of immunotherapeutic strategies, similarly to classical 
chemotherapeutic drugs. In particular, a normalized endothelium ensures the correct 
trafficking of T cells to the tumor bed (28). In fact, tumor angiogenesis contributes to the 
escape of the immune tumor through the immunosuppressive activity exerted by VEGF, 
PGE2, IL-10, and tumor hypoxia. In particular, VEGF acts through both the inhibition of 
lymphocyte adhesion to activated endothelial cells and the systemic effect on immune-
regulatory cell function, including the suppression of DCs maturation, the inhibition of T 
cell development, and the increase of inhibitory immune cells. Therefore, the possibility 
of administering immune checkpoint inhibitors during an anti-angiogenic treatment has 
been studied in different types of cancers according to the hypothesis that anti-angiogenic 
drug-induced normalization of the vessels may improve immunotherapeutic strategies. 


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On the other hand, immune checkpoint inhibitor activation of Th1 cells blocked vessel 
normalization, suggesting the existence of a mutually regulatory circuit. 
It is interesting to note that a combination of small molecules and immune checkpoint 
inhibitors have been evaluated in a mouse model of oral cancer. In this neoplasia, both 
activation of PI3K/mTOR and MEK/ERK pathways promoted the immunosuppressive 
tumor microenvironment [28]. In an immunogenic model of cancer of the oral cavity, 
rapamycin reduced tumor growth in a CD8-dependent manner (28). More recently, Moore 
et al. (28) demonstrated that rapamycin improved IFNγ production by peripheral and 
tumor-infiltrating CD8 T cells in a mouse model of oral cancer. Furthermore, antitumor 
efficacy was enhanced by the CD8 T cell but not by NK cell. Non-inflamed tumor models, 
which represent the low level of response to immune therapies, did not induce T cell or 
NK CD8 cell–mediated antitumor immunity when treated with combinations of targeted 
and immune checkpoint inhibitorss. In other models, antitumor immune responses to PD-
L1 mAb treatment were enhanced when treated with mTOR inhibitors. These data 
suggested that a combination of mTOR and ICIs inhibitors should be evaluated in clinical 
trials setting. An appealing concept is to utilize a tumor targeted rapamycin, nab 
rapamycin (ABI-009) to enhance the efficacy of immune checkpoint inhibitors, specifically 
nivolumab in various cancer types wherein immune checkpoint inhibitors are already 
shown to be effective and are already FDA approved. 
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 (29). 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 (30). 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 (31). 
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 (32) 
• Phosphorylated p-AKT, p-S6, p-4EBP1 expression  (33) 
• biomarkers for the proliferation (Ki-67) and apoptosis (PARP) (31) 


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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 (32). 
Although rapamycin, an oral therapeutic, is an efficacious mTOR inhibitor, it has poor 
solubility, low oral bioavailability, and dose-limiting toxicity (29, 34). 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 (35-39). 
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 (40-42). The most frequently occurring grade 3 or 4 adverse 
events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and 
hypertriglyceridemia (6%) (43). 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 
(44). 
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 
(45). 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 (45, 47). Albumin circulating in the bloodstream can interact 
with gp60 to initiate caveolae-mediated transcytosis to reach tumor cells (48, 49). Indeed, 
nab-paclitaxel transcytosis across the epithelial monolayer was dependent on caveolae 
formation (50). 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 (50). 


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1.2.3. 
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 (51-55). 
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 (56). In addition, recent preclinical study has demonstrated that 
combination of ABI-009 with the Akt inhibitor perifosine induced synergistic antitumor 
activity in multiple myeloma (54). 
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 (53). 
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 (57), 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 (58-60). 
1.2.4. 
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 (42). 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%). 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.  
1.3. 
Nivolumab Background  
Nivolumab is an FDA-approved human monoclonal antibody that blocks the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa 
immunoglobulin that has a calculated molecular mass of 146 kDa (64). 


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1.3.1. 
Nivolumab Mechanism of Action 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, 
inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs 
in some tumors and signaling through this pathway can contribute to inhibition of active 
T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) 
monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-
L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, 
including the anti-tumor immune response. In syngeneic mouse tumor models, blocking 
PD-1 activity resulted in decreased tumor growth (64). 
1.3.2. 
Nivolumab Clinical Studies 
Trial 1 was a multicenter, open-label trial that randomized (2:1) patients with unresectable 
or metastatic melanoma to receive either nivolumab administered intravenously at 3 
mg/kg every 2 weeks or investigator’s choice of chemotherapy, either single-agent 
dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 
3 weeks plus paclitaxel 175 mg/m2 every 3 weeks. Patients were required to have 
progression of disease on or following ipilimumab treatment and, if BRAF V600 mutation 
positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, medical 
conditions requiring systemic immunosuppression, ocular melanoma, active brain 
metastasis, or a history of Grade 4 ipilimumab-related adverse reactions (except for 
endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved 
or were inadequately controlled within 12 weeks of the initiating event. Tumor 
assessments were conducted 9 weeks after randomization then every 6 weeks for the 
first year, and every 12 weeks thereafter.  
Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the 
first 120 patients who received nivolumab in Trial 1 and in whom the minimum duration 
of follow up was 6 months. The major efficacy outcome measures in this population were 
confirmed objective response rate (ORR) as measured by blinded independent central 
review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of 
response.  
Among the 120 patients treated with nivolumab, the median age was 58 years (range: 
25-88), 65% of patients were male, 98% were white, and the ECOG PS was 0 (58%) or 
1 (42%). Disease characteristics were M1c disease (76%), BRAF V600 mutation positive 
(22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior 
systemic therapies for metastatic disease (68%).  
The ORR was 32% (95% confidence interval: 23, 41), consisting of 4 complete responses 
and 34 partial responses in nivolumab-treated patients. Of 38 patients with responses, 33 
patients (87%) had ongoing responses with durations ranging from 2.6+ to 10+ months, 
which included 13 patients with ongoing responses of 6 months or longer.  
There were objective responses in patients with and without BRAF V600 mutation 
positive-melanoma. 


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1.3.3. 
Nivolumab Adverse Events 
The data described in the WARNINGS and PRECAUTIONS section of the nivolumab 
(Opdivo) product information and below reflect exposure to nivolumab in Trial 1, a 
randomized, open-label trial in which 370 patients with unresectable or metastatic 
melanoma received nivolumab 3 mg/kg every 2 weeks (n=268) or investigator’s choice of 
chemotherapy (n=102), either dacarbazine 1000 mg/m2 every 3 weeks or the 
combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 
weeks. The median duration of exposure was 5.3 months (range: 1 day-13.8+ months) 
with a median of eight doses (range: 1 to 31) in nivolumab-treated patients and was 2 
months (range: 1 day-9.6+ months) in chemotherapy treated patients. In this ongoing trial, 
24% of patients received nivolumab for greater than 6 months and 3% of patients received 
nivolumab for greater than 1 year.  
Clinically significant adverse reactions were also evaluated in 574 patients with solid 
tumors enrolled in two clinical trials receiving nivolumab at doses of 0.1 to 10 mg/kg every 
2 weeks, supplemented by immune-mediated adverse reaction reports across ongoing 
clinical trials.   
In Trial 1, patients had documented disease progression following treatment with 
ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded 
patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions 
(except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had 
not resolved or were inadequately controlled within 12 weeks of the initiating event, 
patients with a condition requiring chronic systemic treatment with corticosteroids (>10 
mg daily prednisone equivalent) or other immunosuppressive medications, a positive test 
for hepatitis B or C, and a history of HIV.  
The study population characteristics in the nivolumab group and the chemotherapy group 
were similar: 66% male, median age 59.5 years, 98% white, baseline ECOG performance 
status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 
11% with mucosal melanoma, 73% received two or more prior therapies for advanced or 
metastatic disease, and 18% had brain metastasis. There were more patients in the 
nivolumab group with elevated LDH at baseline (51% vs. 38%).  
• Immune-mediated Grade 2 pneumonitis   
Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with 
nivolumab treatment. Across the clinical trial experience in 574 patients with solid tumors, 
fatal immune-mediated pneumonitis occurred in 0.9% (5/574) of patients receiving 
nivolumab. No cases of fatal pneumonitis occurred in Trial 1; all five fatal cases occurred 
in a dose-finding study with nivolumab doses of 1 mg/kg (two patients), 3 mg/kg (two 
patients), and 10 mg/kg (one patient).  
In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of 
patients receiving nivolumab and none of the 102 patients receiving chemotherapy. 
Immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear 
alternate etiology, occurred in 2.2% (6/268) of patients receiving nivolumab: one with 
Grade 3 and five with Grade 2 pneumonitis. The median time to onset for the six cases 
was 2.2 months (range: 25 days-3.5 months). In two patients, pneumonitis was diagnosed 


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after discontinuation of nivolumab for other reasons, and Grade 2 pneumonitis led to 
interruption or permanent discontinuation of nivolumab in the remaining four patients. All 
six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents 
per day); immune-mediated pneumonitis improved to Grade 0 or 1 with corticosteroids in 
all six patients. There were two patients with Grade 2 pneumonitis that completely 
resolved (defined as improved to Grade 0 with completion of corticosteroids) and 
nivolumab was restarted without recurrence of pneumonitis. 
• Immune-mediated Grade 2-3 colitis  
In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving nivolumab and 
18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis, defined as 
requiring use of corticosteroids with no clear alternate etiology, occurred in 2.2% (6/268) 
of patients receiving nivolumab: five patients with Grade 3 and one patient with Grade 2 
colitis. The median time to onset of immune-mediated colitis from initiation of nivolumab 
was 2.5 months (range: 1-6 months). In three patients, colitis was diagnosed after 
discontinuation of nivolumab for other reasons, and Grade 2 or 3 colitis led to interruption 
or permanent discontinuation of nivolumab in the remaining three patients. Five of these 
six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) 
for a median duration of 1.4 months (range: 3 days-2.4 months) preceding corticosteroid 
taper. The sixth patient continued on low-dose corticosteroids started for another 
immune-mediated adverse reaction. Immune-mediated colitis improved to Grade 0 with 
corticosteroids in five patients, including one patient with Grade 3 colitis retreated after 
complete resolution (defined as improved to Grade 0 with completion of corticosteroids) 
without additional events of colitis. Grade 2 colitis was ongoing in one patient. 
• Immune-mediated hepatitis. Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) greater than 3 and up to 5 times upper limit of normal 
(ULN) or total bilirubin greater than 1.5 and up to 3 times ULN 
In Trial 1, there was an increased incidence of liver test abnormalities in the nibolumab-
treated group as compared to the chemotherapy-treated group, with increases in AST 
(28% vs. 12%), alkaline phosphatase (22% vs. 13%), ALT (16% vs. 5%), and total bilirubin 
(9% vs. 0). Immune-mediated hepatitis, defined as requirement for corticosteroids and no 
clear alternate etiology, occurred in 1.1% (3/268) of patients receiving nivolumab: two 
patients with Grade 3 and one patient with Grade 2 hepatitis. The time to onset was 97, 
113, and 86 days after initiation of nivolumab. In one patient, hepatitis was diagnosed 
after discontinuation of nivolumab for other reasons. In two patients, nivolumab was 
withheld. All three patients received high-dose corticosteroids (at least 40 mg prednisone 
equivalents). Liver tests improved to Grade 1 within 4-15 days of initiation of 
corticosteroids. Immune-mediated hepatitis resolved and did not recur with continuation 
of corticosteroids in two patients; the third patient died of disease progression with 
persistent hepatitis. The two patients with Grade 3 hepatitis that resolved restarted 
nivolumab and, in one patient, Grade 3 immune-mediated hepatitis recurred resulting in 
permanent discontinuation of nivolumab.  
• Immune-mediated nephritis and renal dysfunction. Creatinine greater than 
1.5 and up to 6 times ULN or greater than 1.5 times baseline 


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In Trial 1, there was an increased incidence of elevated creatinine in the nivolumab-
treated group as compared to the chemotherapy-treated group (13% vs. 9%). Grade 2 or 
3 immune-mediated nephritis or renal dysfunction (defined as > Grade 2 increased 
creatinine, requirement for corticosteroids, and no clear alternate etiology) occurred in 
0.7% (2/268) of patients at 3.5 and 6 months after nivolumab initiation, respectively. 
Nivolumab was permanently discontinued in both patients; both received high-dose 
corticosteroids (at least 40 mg prednisone equivalents). Immune-mediated nephritis 
resolved and did not recur with continuation of corticosteroids in one patient. Renal 
dysfunction was ongoing in one patient. 
• Immune-mediated hypothyroidism or hyperthyroidism 
In Trial 1, where patients were evaluated at baseline and during the trial for thyroid 
function, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving 
nivolumab and none of the 102 patients receiving chemotherapy. The median time to 
onset was 2.5 months (range: 24 days-11.7 months). Seventeen of the 21 patients with 
hypothyroidism received levothyroxine. Fifteen of 17 patients received subsequent 
nivolumab dosing while continuing to receive levothyroxine.  
Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving nivolumab and 
1% (1/102) of patients receiving chemotherapy. The median time to onset in nivolumab-
treated patients was 1.6 months (range: 0-3.3 months). Four of five patients with Grade 
1 hyperthyroidism and two of three patients with Grade 2 hyperthyroidism had 
documented resolution of hyperthyroidism; all three patients received medical 
management for Grade 2 hyperthyroidism.  
• Any other severe or Grade 3 treatment-related adverse reactions  
Other clinically significant immune-mediated adverse reactions can occur. Immune-
mediated adverse reactions may occur after discontinuation of nivolumab therapy.  
The following clinically significant, immune-mediated adverse reactions occurred in less 
than 1% of nivolumab-treated patients in Trial 1: pancreatitis, uveitis, demyelination, 
autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis.  
Across clinical trials of nivolumab administered at doses of 3 mg/kg and 10 mg/kg the 
following additional clinically significant, immune-mediated adverse reactions were 
identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, 
and myasthenic syndrome.  
Nivolumab was discontinued for adverse reactions in 9% of patients. Twenty-six percent 
of patients receiving nivolumab had a drug delay for an adverse reaction. Serious adverse 
reactions occurred in 41% of patients receiving nivolumab. Grade 3 and 4 adverse 
reactions occurred in 42% of patients receiving nivolumab. The most frequent Grade 3 
and 4 adverse reactions reported in 2% to less than 5% of patients receiving nivolumab 
were abdominal pain, hyponatremia, increased aspartate aminotransferase, and 
increased lipase. Other adverse events that occurred in >10% of patients were rash, 
pruritus, cough, upper respiratory tract infection, peripheral edema, increased AST, 
increased alkaline phosphatase, hyponatremia, increased ALT, and hyperkalemia, with 


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no Grade 3-4 AE except for rash which was Grade 3-4 in 0.4%. Other clinically important 
adverse reactions in less than 10% of patients treated with nivolumab were:   
Cardiac Disorders: ventricular arrhythmia 
Eye Disorders: iridocyclitis 
General Disorders and Administration Site Conditions: infusion-related reactions 
Investigations: increased amylase, increased lipase   
Nervous System Disorders: dizziness, peripheral and sensory neuropathy   
Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, 
vitiligo, psoriasis.   
1.4. 
Rationale for the Schedule of the Study 
In this study nivolumab will be given once every 3 weeks (D1 of a 3 week cycle) and ABI-
009 will be administered on D8 and D15 of the 3 week cycle starting in Cycle 2 (C2).  
Thus, ABI-009 will be given weekly for 2 weeks with a 1 week break.  
Although nivolumab is approved on a biweekly schedule, in this study, because 
nivolumab is being given in combination with ABI-009 which is administered 2 out of 3 
weeks, a 3 weekly schedule for nivolumab was adopted. In a prior Phase 3 combination 
study with ipililumab, nivolumab 3 mg/kg was given every 3 weeks during the time when 
combination therapy was given (65). In this study, nivolumab and ABI-009 have different 
mechanisms of action. Therefore, it is not expected that the individual toxicities would 
significantly overlap. As a safety precaution, nivolumab will be given every three weeks 
(instead of every 2 weeks) when used in combination with ABI-009. Additionally, 
escalating doses of ABI-009 will start two dose levels below the MTD  of 100 mg/m2 
observed in the Phase 1 study (44), as well as a de-escalation schedule if DLT is noted 
at Dose Level 1 (See Dose Reduction in Section 6). 
Nivolumab acts by blocking PD1, a negative regulator of T cell activation and response, 
thus promoting T cell activation and allowing the immune system to attack the tumor (66). 
Rapamycin suppression of mTOR results in a multitude of effects including a disruption 
of the G1/S transition of the proliferation cycle and results in a mid-to-late G1 arrest (67). 
Rapamycin, by disrupting cytokine signaling that promotes lymphocyte growth and 
differentiation, also promotes the expansion of Treg cells and depletes effector T cells, 
leading to immune suppression (68). It was therefore hypothesized that administering 
anti-PD1 antibody first will allow T cell activation, which will not be blunted by later 
administration of ABI-009. On the other hand, the addition of ABI-009 after anti-PD1 
antibody also allows ABI-009 to exert its antiproliferative activity and potentially to 
increase autophagy for enhanced antigen presentation (30).  In a recent study with 
syngeneic B16 mouse tumor model testing the combination and sequencing of anti-PD1 
antibody and ABI-009, the administration of anti-PD1 antibody for one week before 
combining with ABI-009 demonstrated better antitumor efficacy compared to anti-PD1 
/ABI-009 concurrent treatment or ABI-009 administered for one week before anti-PD1 
antibody [privileged communication by AADi Bioscience Inc]. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
The primary objective of this study is to determine the maximum tolerated dose of ABI-
009 when used in combination with nivolumab in advanced UPS, liposarcoma, 
osteosarcoma, chondrosarcoma and Ewing sarcoma.  
2.1.2. 
Secondary Objectives 
The secondary objectives are to investigate the disease control rate (DCR), progression 
free survival (PFS), recurrence-free survival (RFS) and overall survival (OS) using 
nivolumab/ABI-009 combination therapy in advanced Ewing’s sarcoma, PEComa, 
epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung 
cancer, urethelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma 
of head and neck, hepatocellular carcinoma, classical Hodgkin’s lymphoma, MSI-
H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to 
mTOR inhibitors.  
2.1.3. 
Exploratory Objectives 
• To correlate DCR based on Immune-related Response Criteria (irRECIST) with 
that based on RECIST v1.1. 
• To correlate DCR with PD-L1 and other biomarker expression in patients’ tumors 
• To correlate DCR with PTEN mutation in patient’s archived tumor 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
Maximum tolerated dose (MTD) 
2.2.2. 
Secondary Endpoints 
The secondary endpoints are  
• Disease control rate (DCR), progression free survival (PFS), recurrence-free 
survival (RFS) as determined by the institution’s radiologic assessment using 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and irRECIST criteria 
(Hodi et al., 2016); and overall survival (OS). 
• PFS rate at 3, 6, 9, and 12 months, RFS at 4 months, median PFS, and median 
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 PFS rate at 4 months, 
median PFS, and OS. Recurrence-free survival (RFS) defined as progression free 


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survival + absence of disease progression or recurrence after surgical resection 
has been added to the secondary endpoints to obviate this bias.  
2.2.3. 
Exploratory Endpoints 
• Correlation between DCR based on Immune-related Response Criteria (irRECIST) 
with that based on RECIST v1.1. 
• Correlation between DCR with PD-L1 and other biomarker expression in patients’ 
tumors.  
• Correlation between DCR and PTEN mutation in patient’s archived tumor 
2.3. 
Study Design 
This is an open label, dose-seeking phase 1/2 study using a defined dose of nivolumab 
and escalating doses of ABI-009 given intravenously.  
I. Dose Escalation Phase 1 Part of Study:  The study will employ the standard “cohort 
of three” design (Storer, 1989). Three patients are treated at each dose level with 
expansion to six patients per cohort if DLT is observed in one of the three initially-enrolled 
patients at each dose level. If no DLT occurs after 2 doses, escalation to the next dose 
level will be permitted. The maximum tolerated dose is defined as the highest safely 
tolerated dose, where not more than one patient experienced DLT, with the next higher 
dose level having at least two patients who experienced DLT. Patients in the dose 
escalation study may continue treatment at their designated dose levels up to eighteen 
3-week treatment cycles or until significant disease progression or unacceptable toxicity 
occurs. No intra-patient dose escalation will take place. 
Dose of nivolumab: 3 mg/kg IV over 30 min. q 3 weeks  
NB: ABI-009 will start after 2nd Nivo dose, and will be administered on D8 and D15 
beginning in C2. 
Dose of ABI-009: Escalating doses IV over 30 min for 2 of every 3 weeks: 
 
Treatment Cycle        # Pts.      Dose Level      Dose, mg/m2       
 
Every 3 weeks             3-6                 I                        56                       
Every 3 weeks             3-6                II                        75 
                         
Every 3 weeks             3-6               III                      100 
 
Note: DLT includes any > Grade 3 colitis, hepatitis, or pneumonitis, any Grade 1-2 colitis, 
hepatitis or pneumonitis that recurs, worsens or persists with oral steroids longer than 14 
days, symptoms of adrenal crisis, any Grade 4 hematologic toxicity or any        > Grade 
3 non-hematologic toxicity.  
 
II. Expansion Phase 2 Part of Study: Following dose escalation, an additional 22-28 
patients will receive ABI-009 at the MTD and defined doses of nivolumab to assess overall 
safety and potential efficacy in a greater number of patients. Patients in the expansion 


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phase of the study may continue treatment up to 18 3-week treatment cycles or until 
significant disease progression or unacceptable toxicity occurs. 
The study will be conducted in compliance with International Conference on 
Harmonisation (ICH) Good Clinical Practices (GCPs). 
Surgical Resection: After three or more treatment cycles, the principal investigator may 
recommend surgical debulking, complete surgical removal or a biopsy. If residual disease 
is present either by histopathological examination or by CT scan/MRI, repeat treatment 
cycles may be given 2-4 weeks after surgery, if the surgical incision has healed, and if 
the patient has < grade I toxicity.  
 
Resected or biopsied tumors will be analyzed for the effects of this dual therapy on 
disease control rate, and immune cell trafficking in the tumor microenvironment. Fresh 
and paraffin embedded tissue blocks will be analyzed by FACS for PD-L1 and other 
biomarkers, including Tregs, CD8+, CD4+ cells etc. Immunohistochemistry for cyclin G1, 
cyclin D1 and Ki67 will be conducted to determine the tumor's proliferative state. 
Histopathologic examination for tumor necrosis and mitotic index will also be determined. 
 
Conditions for Continuation of Treatment in the Presence of Increased Tumor 
Size by CT scan or MRI Indicating Progressive Disease by RECIST v1.1: 
Treatment may be continued if: 
1. There are no signs or symptoms indicating unequivocal progression. 
2. There is no worsening of ECOG score attributable to progressive disease. 
3. There is no tumor growth at critical sites that is life-threatening. 
4. Patient signs an informed consent that he/she is aware of alternative therapies but  
    wishes to defer these therapies. 
5. There is clinical benefit, as determined by investigator 
2.4. 
Study Duration  
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 or 
nivolumab.  
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 or nivolumab.   


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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. 
2.5. 
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 or nivolumab 
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 or nivolumab.  
Primary analysis for this study will occur after all patients have either completed the 
study or completed 12 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, 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 
nivolumab, 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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3. 
STUDY POPULATION 
3.1. 
Number of Patients 
The anticipated enrollment into this study will be approximately 12-18 patients for the 
Phase 1 part of the study and approximately 22-28 evaluable patients for the Phase 2 
part of the study. The rationale for the number of patients is detailed in Section 8. 
The investigator will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate, date, and 
outcome of the screening process (e.g., enrolled into study, reason for ineligibility, or 
refused to participate).   
Before any study-specific procedure, the appropriate written informed consent must be 
obtained (see Section 11.5). 
3.2. 
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 Ewing’s sarcoma, 
PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung 
cancer, small cell lung cancer, urethelial carcinoma, melanoma, renal cell 
carcinoma, squamous cell carcinoma of head and neck, hepatocellular 
carcinoma, classical Hodgkin’s lymphoma, MSI-H/dMMR metastatic 
colorectal cancer, and tumors with genetic mutations sensitive to mTOR 
inhibitors, that is either metastatic or locally advanced and for which surgery 
is not a recommended option. 
2. Patients must have one or more measurable target lesions by CT scan or 
MRI. Measurable disease by RECIST v1.1, confirmed by investigator. 
3. Previously treated patient with Ewing’s sarcoma, PEComa, epithelioid 
sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell 
lung cancer, urethelial carcinoma, melanoma, renal cell carcinoma, 
squamous cell carcinoma of head and neck, hepatocellular carcinoma, 
classical Hodgkin’s lymphoma, MSI-H/dMMR metastatic colorectal cancer, 
and tumors with genetic mutations sensitive to mTOR inhibitors, if treatment 
is completed after 5 half-lives or ≥28 days prior to enrollment, whichever is 
shorter. 
4. Eligible patients, 12-17 years (>40 kg) or 18 years old or older, with Eastern 
Cooperative Oncology Group (ECOG) performance status 0 or 1. 
5. 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 


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b. AST/ALT ≤2.5 x ULN (≤5 x ULN if attributable to liver metastases); alk 
phos < 3 x ULN (patients with alk phos >3ULN will be allowed if due to bone 
metastases) AST ≤2.5 x ULN (≤5 x ULN if attributable to liver metastases) 
c. serum creatinine ≤1.5 x ULN 
6. 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.  
7. Serum triglyceride <300 mg/dL; serum cholesterol < 350 mg/dL. 
8.  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. 
9.  Life expectancy of >3 months, as determined by the investigator. 
10.  Ability to understand and sign informed consent. 
11.  Willingness and ability to comply with scheduled visits, laboratory tests, and 
other study procedures. 
3.3. 
Exclusion Criteria  
A patient will not be eligible for inclusion in this study if any of the following criteria apply: 
1. 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. 
2. Active gastrointestinal bleeding. 
3. Pre-existing thyroid abnormality is allowed provided thyroid function can be 
controlled with medication. 
4. 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 


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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). 
5. 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. 
6. 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). 
7. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate 
therapy. 
8. Unstable coronary artery disease or myocardial infarction during preceding 6 
months. 
9. Receiving any concomitant antitumor therapy. 
10. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary 
hypertension. 
11. 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.  
12. Known Human Immunodeficiency Virus (HIV). 
13. Active Hepatitis B or Hepatitis C.  
14. Non-oncology vaccine therapy used for prevention of infectious disease within 
4 weeks of trial enrollment 
15. Autoimmune disease including rheumatoid arthritis, systemic progressive 
sclerosis (scleroderma), systemic lupus erythematosus, autoimmune 
vasculitis and motor neuropathy considered to be of autoimmune origin (e.g. 
Guillain-Barre Syndrome) 
16. Systemic immunosuppression, including HIV positive status with or without 
AIDS 
17. Skin rash (psoriasis, eczema) affecting > 25% body surface area 
18. Inflammatory bowel disease (Crohn’s or ulcerative colitis) 
19. Ongoing or uncontrolled diarrhea within 4 weeks of trial enrollment 
20. Recent history of acute diverticulitis, intraabdominal abscess or 
gastrointestinal obstruction within 6 months of trial enrollment, which are 
known risk factors for bowel perforation  
21. Current, active or previous history of heavy alcohol abuse  
22. Pituitary endocrinopathy and Adrenal insufficiency or excess 


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4. 
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 
Day 15 
 
General Assessments  
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 
X f 
 
BSA Calculation 
 
X j 
 
 
 
 
Prior/Concomitant Medication Evaluation g 
X 
X 
X 
X 
Until 28 days after the 
last dose of IP 
 
Prior/Concurrent Procedures Evaluation g 
X 
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 
 
  
 
 
 
Survival status  
 
 
 
 
 
X 
Adverse Events  
 
Continuous starting from signing of Informed Consent until 28 days after last dose of IP 
Dexamethasone (every cycle) 
 
 
X 
 
 
 
Nivolumab Dosing 
 
X 
 
 
 
 
ABI-009 Dosing: To Start after 2nd Nivo dose 
 
 
X 
X 
 
 
 
Local Laboratory Assessments 
Clinical Chemistry Panel 
X 
X 
X 
X 
X 
 
CBC, Differential, Platelet Count 
X 
X 
X 
X 
X 
 


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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 
Day 15 
PT, PTT, INR 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
Thyroid function 
X 
X 
 
 
 
 
HIV, HBV sAg, HBV cAb, HCV Ab 
X 
 
 
 
 
 
Fasting Lipids 
X 
X 
 
 
 
 
Trough rapamycin level k 
 
 
 
 
 
 
Immunohistochemistry for PTEN mutation in 
archived tumor 
X 
 
 
 
 
 
 
Imaging and Efficacy Assessments 
CT/MR l 
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 except for thyroid and fasting lipids every 12 weeks. 
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, and as clinically indicated following standard of care procedures. 
j. 
 Calculated ONLY on C1/D1; to be recalculated only if the weight changes by > 10% in subsequent cycles. 
k. 
 Trough levels of rapamycin will be obtained immediately prior to ABI-009 infusion at Day 15 of the second and third cycles of ABI-009, a week after the first dose in both cycles. 
l. 
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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5. 
PROCEDURES 
5.1. 
Screening Evaluations 
This study will be conducted at a single center, the Sarcoma Oncology Research Center, 
Santa Monica CA, USA. 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 have signed the informed consent.  
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 
• Vital signs (eg, blood pressure, pulse, respiration rate, temperature) 
• ECG   
• Adverse event assessment 
• Local Laboratory Assessments: chemistry, complete blood count (CBC), 
differential, platelet count, coagulation, urinalysis, thyroid function, pregnancy 


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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 2 weeks prior to study day 1, preferably 
as close to the day of enrollment as possible 
• Immunohistochemistry for PTEN mutation on patient’s archived tumor  
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 (CRF). 
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 4.    
5.2. 
Treatment Period 
All product administration (investigational or otherwise) 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 or up to 18 3-week treatment cycles. 
5.2.1. 
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 
• 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 (every 12 weeks) 
• Fasting lipids (every 12 weeks) 
• Adverse Event assessment 
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, 


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coagulation, urinalysis, pregnancy test (women of child-bearing potential, includes tubal 
ligation)  
5.2.2. 
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 
• Clinical chemistry panel (including but not limited to sodium, potassium, 
chloride, glucose, alkaline phosphatase (ALP), AST/SGOT, ALT/SGPT, serum 
albumin) 
• Trough levels of rapamycin will be obtained immediately prior to ABI-009 
infusion at Day 15 of second and third cycles of ABI-009. 
• Adverse Event assessment 
5.2.3. 
Day 15 Assessment 
The following assessments will be performed on Day 15 of each cycle, unless otherwise 
specified: 
• Concomitant medication and procedures evaluation 
• Vital signs 
• CBC, differential and platelet count 
• Adverse Event assessment 
5.2.4. 
Response Assessment  
Tumor response will be assessed by CT or MRI scan of the chest, abdomen, and pelvis 
(CAP); image preparation and evaluation will follow the specifications provided in the 
RECIST version 1.1. Immune RECIST (irRECIST) will also be obtained. 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: 
• ≤2 weeks prior to C1D1 (screening) 
• followed by every 6 weeks for the first year; then every 12 weeks until disease 
progression or unacceptable toxicity. 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. Determination of disease progression for clinical 
management of patients on study will be assessed at the local site. If an initial observation 


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of objective response (CR or PR) is made, a confirmation scan should be done at 6 weeks 
after initial observation.  
 
Conditions for Continuation of Treatment in the Presence of Increased Tumor 
Size by CT scan or MRI Indicating Progressive Disease by RECIST v1.1: 
Treatment may be continued if: 
1. There are no signs or symptoms indicating unequivocal progression. 
2. There is no worsening of ECOG score attributable to progressive disease. 
3. There is no tumor growth at critical sites that is life-threatening. 
4. Patient signs an informed consent that he/she is aware of alternative therapies but 
wishes to defer these therapies. 
5. There is clinical benefit, as determined by investigator 
 
Table 3.  
Analyte Listing 
Chemistry 
Hematology 
Coagulation 
Urinalysis 
Other Labs 
Sodium 
WBC 
PT 
Specific gravity Pregnancy test 
Potassium 
RBC 
PTT 
pH 
 
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 
 
 
PD-1\PD-L1 
Total bilirubin 
-Monocytes 
 
 
 
Alkaline phosphatase -Eosinophils 
 
 
 
AST (SGOT) 
-Basophils 
 
 
 
ALT (SGPT) 
 
 
 
 
Amylase 
 
 
 
 
Lipase 
 
 
 
 
 
5.3. 
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 or 


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nivolumab. 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 (Table 2): 
• 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  
5.4. 
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.  


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6. 
DESCRIPTION OF STUDY TREATMENTS (ABI-009/NIVO) 
6.1. 
ABI-009/Nivolumab Dosage, Administration, and Schedule 
For the Phase 1 part of study, patients will receive nivolumab 3 mg/kg as IV infusion over 
60 min every 3 weeks, followed by escalating doses of ABI-009 56,  75, 100 mg/m2 for 2 
of every 3 weeks by IV infusion over 30 minutes. ABI-009 will start on Day 8 of Cycle 2. 
If DLT develops in more than 1 patient at Dose 56 mg/m2, the dose will be de-escalated to 45 
mg/m2 and to 30 mg/m2 if DLT develops at 45 mg/m2. Patients will continue therapy until 
unequivocal clinical disease progression, unacceptable toxicity, or until in the opinion of 
the investigator the patient is no longer benefiting from therapy, or at the patient’s 
discretion.  
For the Phase 2 part of study, patients will receive nivolumab 3 mg/kg as IV infusion over 
30 min every 3 weeks, followed by ABI-009 at the MTD dose for 2 of every 3 weeks by IV 
infusion over 30 minutes. ABI-009 will start on Day 8 of Cycle 2. Patients will continue 
therapy until unequivocal clinical disease progression, unacceptable toxicity, or until in 
the opinion of the investigator the patient is no longer benefiting from therapy, or at the 
patient’s discretion.  
6.2. 
ABI-009 Dose Modification and Stopping Rules 
6.2.1. 
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. 
If a Grade 4 hematologic toxicity occurs, the dose of ABI-009 is held until toxicity resolves 
to Grade 1 or less. The dose of ABI-009 is then modified according to the dose 
modification section. If a Grade 3 non-hematologic toxicity occurs, both nivolumab and 
ABI-009 are withheld until toxicity resolves to Grade 1 or less. The dose of ABI-009 is 
then modified according to the dose modification section. Nivolumab has no dose 
modification. 
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. 
During the Phase 2 part of the study, doses of ABI-009 will be reduced for hematologic 
and other toxicities. Two levels of dose modifications are permitted according to the 
criteria below. If MTD is determined to be 56 mg/m2, dose reductions will occur 
sequentially (45 mg/m2 and 30 mg/m2), there should be no direct reduction by two dose 


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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 
  1 
Initial Dose: 56 mg/m2 
-1 (first dose reduction) 
 45 mg/m2 
-2 (second dose reduction) 
 30 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 
 
6.2.2. 
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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6.2.2.1. 
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) 
6.2.2.2. 
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: 
• Elevation of either AST or ALT according to the following schedule: 


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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. 
6.2.2.3. 
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 6.2.1) should never be rechallenged. 
6.2.3. 
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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6.3. 
Nivolumab Dose Modification and Stopping Rules 
6.3.1. 
Dose Modification and Stopping Rules  
 
Nivolumab (Opdivo®); see product information at www.accessdata.fda.gov) 
Withhold nivolumab for any of the following:  
• Immune-mediated Grade 2 pneumonitis   
Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a 
dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, 
followed by corticosteroid taper. Permanently discontinue nivolumab for severe (Grade 
3) or life-threatening (Grade 4) pneumonitis and withhold nivolumab until resolution for 
moderate (Grade 2) pneumonitis 
• Immune-mediated Grade 2-3 colitis  
Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 
to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe 
(Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 
to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate 
(Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs 
despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone 
equivalents. Withhold nivolumab for Grade 2 or 3 immune-mediated colitis. Permanently 
discontinue nivolumab for Grade 4 colitis or for recurrent colitis upon restarting 
nivolumab. 
• Immune-mediated hepatitis. Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) greater than 3 and up to 5 times upper limit of normal 
(ULN) or total bilirubin greater than 1.5 and up to 3 times ULN 
Monitor patients for abnormal liver tests prior to and periodically during treatment. 
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for 
Grade 2 or greater transaminase elevations, with or without concomitant elevation in 
total bilirubin. Withhold nivolumab for moderate (Grade 2) and permanently discontinue 
nivolumab for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis 
• Immune-mediated nephritis and renal dysfunction. Creatinine greater than 
1.5 and up to 6 times ULN or greater than 1.5 times baseline 
Monitor patients for elevated serum creatinine prior to and periodically during treatment. 
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents 
followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation 
and permanently discontinue nivolumab. For severe (Grade 3) or moderate (Grade 2) 
serum creatinine elevation, withhold nivolumab and administer corticosteroids at a dose 
of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if 
worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 
mg/kg/day prednisone equivalents and permanently discontinue nivolumab. 
 


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• Immune-mediated hypothyroidism or hyperthyroidism 
There are no recommended dose modifications for hypothyroidism or hyperthyroidism.  
Monitor thyroid function prior to and periodically during treatment. Administer hormone 
replacement therapy for hypothyroidism. Initiate medical management for control of 
hyperthyroidism. There are no recommended dose adjustments of nivolumab for 
hypothyroidism or hyperthyroidism. 
• Any other severe or Grade 3 treatment-related adverse reactions  
For any suspected immune-mediated adverse reactions, exclude other causes. Based 
on the severity of the adverse reaction, withhold nivolumab, administer high-dose 
corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon 
improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over 
at least 1 month. Consider restarting nivolumab after completion of corticosteroid taper 
based on the severity of the event. 
6.3.2. 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Resume nivolumab in patients whose adverse reactions recover to Grade 0-1. 
Permanently discontinue nivolumab for any of the following: 
• Any life-threatening or Grade 4 adverse reaction 
• Grade 3 or 4 pneumonitis  
• Grade 4 colitis  
• AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN  
• Creatinine greater than 6 times ULN 
• Any severe or Grade 3 treatment-related adverse reaction that recurs 
• Inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
• Persistent Grade 2 or 3 treatment-related adverse reactions that do not recover 
to Grade 0-1 within 12 weeks after last dose of nivolumab 
 
 


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7. 
STUDY DRUG MANAGEMENT  
7.1. 
Description of Study Drugs  
7.1.1. 
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. 
7.1.2. 
Nivolumab Packaging, Labeling and Storage 
Nivolumab (Opdivo) is a human monoclonal antibody that blocks the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2 (64). Nivolumab is an IgG4 kappa immunoglobulin 
that has a calculated molecular mass of 146 kDa.  
Nivolumab (OPDIVO) is a sterile, preservative-free, non-pyrogenic, clear to opalescent, 
colorless to pale-yellow liquid that may contain light (few) particles. OPDIVO injection for 
intravenous infusion is supplied in single-use vials. Each mL of OPDIVO solution contains 
nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), 
sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, 
USP. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6. 
Nivolumab (OPDIVO) is available as 40 mg/4 ml and 100 mg/10 ml single use vials. Store 
nivolumab under refrigeration at 2°C to 8°C (36°F-46°F). Protect nivolumab from light by 
storing in the original package until time of use. Do not freeze or shake. 
7.2. 
ABI-009 and Nivolumab Accountability, Disposal, and Compliance 
For ABI-009, 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. 
For ABI-009, 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 


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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 CRF 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. 
For Nivolumab, the Investigator, or designee, shall record the dispensing of study drug 
to patients. The study drug record will be made available to AADi or authorized AADi-
designated monitoring personnel for the purpose of accounting for the use of the drug. 
Accurate recording of all nivolumab administration will be made in the appropriate 
section of the patient’s CRF 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. 
7.3. 
ABI-009 Reconstitution 
NOTE: It is not a requirement to use filter needles in the preparation, or in-line filters 
during the administration of ABI-009. In any event, filters of pore size less than 15 microns 
(15 µm) must not be used. 
ABI-009 will be reconstituted by appropriate study personnel 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).  


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• 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) 
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. 


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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). 
7.4. 
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. Investigator or designee will be 
responsible for drug inventory, drug accountability, and disposition of unused study drug.  
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. 
7.5. 
Nivolumab (Opdivo) Reconstitution 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. 
Discard the vial if the solution is cloudy, is discolored, or contains extraneous particulate 
matter other than a few translucent-to-white, proteinaceous particles. Do not shake the 
vial (64).  
Preparation of nivolumab: 
• Withdraw the required volume of nivolumab and transfer into an intravenous 
container. 
• Dilute nivolumab with 100 ml 0.9% Sodium Chloride Injection, USP to prepare an 
infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. 
• Mix diluted solution by gentle inversion. Do not shake. 
• Discard partially used vials or empty vials of nivolumab. 
− Storage of Infusion  
− The product does not contain a preservative.  
After preparation, store the nivolumab infusion either: 
• at room temperature for no more than 4 hours from the time of preparation. This 
includes room temperature storage of the infusion in the IV container and time for 
administration of the infusion or 
• under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours from the 
time of infusion preparation. 
• Do not freeze.  
 


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Administration of nivolumab: 
• Administer the infusion over 60 minutes through an intravenous line containing a 
sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer 
to 1.2 micrometer).   
• Do not coadminister other drugs through the same intravenous line.  
• Flush the intravenous line at end of infusion.   
7.6. 
Concomitant Medications and Procedures 
Dexamethasone, 10 mg IV, will be given on D8 of every cycle, beginning Cycle 2, to 
preempt or reduce the incidence/severity of pneumonitis and/or hepatitis with combined 
use of nivolumab and ABI-009. 
All concomitant treatments, including blood and blood products, must be reported on the 
CRF. Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those listed 
in Section 7.8. 
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 CRF(s). 
7.7. 
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 CRF. 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 CRF. 
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.  
7.8. 
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: 


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• 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.  
• 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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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Study Endpoints 
Primary Endpoint:  
• MTD 
Secondary Endpoint(s):  
• Disease control rate (DCR), ORR (CR+ PR) 
• Progression-free survival  
• Progression-free survival rate at 3,6,9,12 months 
• Overall survival  
• Incidence and grade of treatment-emergent AEs 
Exploratory Endpoint(s): 
• Correlation of response based on RECIST v1.1 and irRECIST 
• Correlation between response and PD-L1 expression in patients’ tumors 
• Correlation between DCR and PTEN mutation in patient’s archived tumor 
8.2. 
Safety Analysis 
Demographic and baseline information (e.g., extent of prior therapy) on study patients 
will be tabulated. The number of patients studied for the Phase 1 part of study could 
range from 12 to 18 evaluable patients, and 22-28 evaluable patients for the Phase 2 
part of the study.   
For the Phase 1 part of the study, the following information will be reported for adverse 
events observed in the study: dose level, type (organ affected or laboratory 
determination, such as absolute neutrophil count), severity (by NCI Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 and most extreme 
abnormal values for laboratory determinations) and relatedness to study treatment.  For 
each dose the number and percentage of patients experiencing any grade 3, 4, or 5 
adverse event will be reported, as well as the number and percentage of patients who 
experienced selected specific types of adverse events.  In addition, the DLTs will be 
summarized by dose level and the MTD will be determined. 
The following table gives the probability of dose escalation at a single dose level as a 
function of the true probability of DLT at that level using the cohorts of 3 design 
(Objective #1) (2).   
 
 
 
 
 
 


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Table 1.  Probability of Dose Escalation 
True Rate of DLT (%) 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 
30 
0.49 
40 
0.31 
50 
0.17 
 
For the Phase 2 part of the study, the entire treated population (Full Analysis Set) will be 
the analysis population for all safety analyses. Adverse events will be coded using the 
NIH CTCAE v4.03. 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 all 
patient groups together (metastatic and locally advanced). Although this study will not 
be large enough to allow firm conclusions about safety or efficacy, it will provide 
preliminary data on safety and efficacy that will be useful in planning future studies. 
Frequency tables, graphs, and summary statistics will be used for outcome data.  
Patient incidence of all treatment-emergent AEs will be tabulated. Tables of fatal adverse 
events, serious adverse events, treatment-related AEs, and adverse events leading to 
withdrawal from investigation product will also be provided.  
For select laboratory parameters, changes of laboratory values over time (e.g., 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.  
For ABI-009 and nivolumab exposure, summary statistic will be provided for total number 
of doses, average dose administered, and duration of each treatment. 
8.3. 
Efficacy Analysis  
The Efficacy Analysis Dataset includes all enrolled patients with measurable tumor per 
RECIST v1.1 at baseline who receive at least two doses of ABI-009 and had a follow-up 
CT scan/MRI.  
The disease control rate (DCR; CR+PR+SD), objective response rate (ORR; CR + PR), 
progression free survival (PFS), recurrence-free survival (RFS) will be assessed by an 
local radiologic assessment using Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. 


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The focus of the study is to estimate the DCR in patients treated with ABI-009 and 
nivolumab. Patients who progress before receiving ABI-009 will be replaced, and will not 
be included in the statistical analysis. The number and percentage of patients achieving 
disease control (CR, PR or SD) will be summarized.  
Analysis of other efficacy endpoints, PFS at 4 months, RFS at 4 months, median PFS, 
median RFS and median OS will be assessed for all subtypes together, and separately 
in the five sarcoma subtypes with metastatic disease and locally advanced disease. 
Patients may be stratified further as locally advanced or metastatic. 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 PFS at 
4 months, median PFS, and OS. Recurrence-free survival (RFS) defined as progression 
free survival + absence of disease progression or recurrence after surgical resection has 
been added to the secondary endpoints to obviate this bias.  
PFS, RFS and OS will be summarized using Kaplan-Meier (KM) analysis. The number of 
patients in each category is expected to be small; therefore, PFS at 4 months, RFS at 4 
months, median PFS, and median OS for these patients will be summarized by 
descriptive statistics. 
8.4. 
Exploratory Analysis 
DCR based on RECIST v1.1 will be correlated with DCR based on Immune-related 
Response Criteria (irRECIST) and summarized by descriptive statistics and comparative 
KM analysis. 
PD-L1 and other biomarker expression in patients’ tumors will be correlated with DCR 
and summarized by descriptive statistics. 
DCR will be correlated with presence of PTEN mutation in patient’s archived tumor and 
summarized by descriptive statistics. 
8.5. 
Covariates and Subgroups 
Up to 20 clinical indications will be studied , including Ewing’s sarcoma, PEComa, 
epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, small cell lung 
cancer, urethelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma 
of head and neck, hepatocellular carcinoma, classical Hodgkin’s lymphoma, MSI-
H/dMMR metastatic colorectal cancer, and tumors with genetic mutations sensitive to 
mTOR inhibitors, as well as those with metastatic disease and those with locally 
advanced disease for which surgery is not an option. The subgroups of patients will be 
assessed together and as subgroups for the efficacy endpoints, 
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) 


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• Time from initial diagnosis to enrollment 
8.6. 
Sample Size Considerations 
The analyses of all study objectives is descriptive and hypothesis generating in nature.  
The sample size will not be enough to make any statistical conclusions about efficacy or 
safety, but will be useful for planning future Phase 2 clinical trials. 
8.7. 
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. 
8.8. 
Planned Methods of Analysis 
8.8.1. 
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. 
8.8.2. 
General Considerations 
The secondary efficacy endpoint, DCR, will be determined by a local radiologic 
assessment.   
The primary analysis will evaluate the DCR in patients treated with ABI-009 and 
nivolumab by providing the number and proportion of patients achieving disease control 
along with an exact binomial 95% CI for the proportion.  
DCR is defined as the proportion of patients who achieve a confirmed CR, PR or SD per 
RECIST v1.1. 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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8.8.3. 
Other Secondary Efficacy Endpoints 
Analysis of other secondary efficacy endpoints PFS at 4 months, RFS at 4 months, 
median PFS, and median OS will be done separately for the 5 sarcoma subtypes groups. 
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.  
Recurrence-free survival (RFS) is defined as the time from the first dose date to the first 
observation of a disease progression or recurrence/progression after surgical resection 
of tumor, or death due to any cause.  If a patient has not progressed or died by the data 
cutoff date, the RFS 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.  


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9. 
MONITORING, RECORDING AND REPORTING OF ADVERSE 
EVENTS  
9.1. 
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 (58, 59). 
9.2. 
Toxicities of Nivolumab 
Nivolumab is an FDA approved monoclonal antibody for the treatment of advanced 
melanoma, non small cell lung cancer, renal cell carcinoma and bladder cancer. The 
toxicities of nivolumab are immune-related adverse events including immune-mediated 
pneumonitis, hepatitis, endocrinopathies and visual disorders. More details and known 
precautions, 
warnings 
and 
AEs 
are 
found 
in 
the 
product 
information 
(www.accessdata.fda.gov). 
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 CRF 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 6.2.3 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 CRF and in the patient’s source documents. All 


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SAEs must be reported to AADi Drug Safety within 24 hours of the investigator’s 
knowledge of the event by facsimile, or other appropriate method, using the SAE Report 
Form, or approved equivalent form. 
The investigator’s clinical judgment is used to determine whether a patient is to be 
removed from treatment due to an AE. The investigator is responsible for ensuring that 
all AEs observed by the investigator or reported by the patient that occur after the first 
dose of IP through the EOT Visit are reported using the applicable CRF (eg, Adverse 
Event Summary CRF).  
9.3. 
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.  
9.4. 
Serious Adverse Events 
9.4.1. 
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 


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(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.   
9.4.2. 
Reporting Procedures for Serious Adverse Events 
All suspected unexpected serious adverse reactions (SUSARs) must be reported by the 
Investigator to their IRB in writing, and to the FDA within 7 days as required by law. 
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 CRF.  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. 
9.5. 
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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10. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND 
STUDY 
10.1. 
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 CRF) 
The reason for treatment discontinuation should be recorded in the CRF and in the source 
documents. 
10.2. 
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 CRF) 
The reason for study discontinuation should be recorded in the CRF 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 (e.g., 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. 
10.3. 
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 Investigational 
Product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.    


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Patients may be eligible for continued treatment with AADi’s Investigational Product 
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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11. 
REGULATORY OBLIGATIONS 
11.1. 
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 the investigator to AADi. 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.   
11.2. 
Institutional Review Board/Independent Ethics Committee  
A copy of the protocol, proposed informed consent form, other written patient information, 
and any proposed advertising material must be submitted to the IRB for written approval. 
A copy of the written approval of the protocol and informed consent form must be received 
by AADi before recruitment of patients into the study and shipment of AADi IP. 
The investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
investigator is to notify the IRB of deviations from the protocol or SAEs occurring at the 
site and other AE reports received from AADi, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB approval [IRBs only]/renewal 
[IRBs and IECs] throughout the duration of the study. Copies of the investigator’s reports 
and the IRB continuance of approval must be sent to AADi. 


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11.3. 
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. 
 
11.4. 
Protocol Amendments   
If investigator amends the protocol, agreement from AADi 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. 
11.5. 
Termination of the Study 
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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12. 
DATA HANDLING AND RECORDKEEPING 
12.1. 
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 CRFs or CD-ROM. 
12.2. 
Data Management 
Data will be collected via CRF 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. 
12.3. 
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. 
12.4 Research Use of Fresh and Stored Human Samples, Specimens or Data 
• Intended Use: Samples and data collected under this protocol will be used to study 
the effects of combination therapy with ABI-009, an mTOR inhibitor that affects the 
differentiation of M1 and M2 macrophages in the tumor microenvironment (TME), 
and a immune checkpoint inhibitor, nivolumab, that inhibits CTLA4 and PD-1 and 
ligands in the TME. No genetic testing will be conducted. 
• Resected or biopsied tumors that are > than 500 mm3 will be collected and cut into 
two pieces. One piece of tumor will be placed in media, processed and analyzed 
by flow cytometry (FACS). The second piece will be placed in 10% neutral-buffered 
formalin and later processed to formalin-fixed paraffin-embedded (FFPE) blocks. 
Tumors that are < 500 mm3 in volume will be not be cut and the whole tumor will 
be used for FACS analysis.   
• For biomarker studies, flow cytometry analysis will be for human CD45, CD3, CD4, 
CD8, CD56, LAG-3, PD-1 and PD-L1 markers. Cell suspensions will be divided in 
two tubes, and each tube will be analyzed independently for the individual set of 
markers. Tube 1: CD45, CD3, CD4, CD8, CD56, PD-1, PD-L1, viability. Tube 2: 


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CD45, CD3, CD4, CD8, CD56, LAG-3, CD19 or CD20 (B cell marker), TIM3, 4-
IBB, and FoxP3 regulatory T cells. 
• Histopathologic examination of resected or biopsied tumors will be conducted, the 
degree of tumor necrosis and mitotic index will be assessed, and 
immunohistochemical analysis for expression of PD-1, PD-L1, CD8+, CD4+, 
CD19, CD20, CD45, NK, Ki67, cyclin G1, cyclin D1 will be conducted.   
• Storage: Access to stored samples will be limited using a locked freezer.  Samples 
and data will be stored using codes assigned by the investigators.  Data will be 
kept in password-protected computers. Only investigators will have access to the 
samples and data. 
• Tracking: Data will be tracked using a secure database system (e.g. Merge eCOS). 
• Disposition at the completion of the study: All stored samples will be archived at 
the clinical site. Study participants who request destruction of samples will be 
notified of compliance with such request and all supporting details will be 
maintained for tracking. 
12.5 Future Use of Stored Specimens 
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. Data collected for this study will be 
analyzed and stored at the clinical site. After the study is completed, the de-identified, 
archived data will be transmitted to and stored in a secure database under the 
supervision of the principal investigator, for use by other researchers including those 
outside of the study. Permission to transmit data to the secure data base will be 
included 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 
(e.g., the scientific rationale for experimentation with a certain sample type no longer 
justifies keeping the sample). The patient has no commercial rights to the products and 
has no commercial rights to the data, information, discoveries, or derivative materials 
gained or produced from the sample.  
12.6 Sample Storage and Destruction 
Any blood or tumor 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 


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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.   
Results from this analysis are to be documented and maintained, but are not necessarily 
reported as part of this study.  
The records should be retained by the Investigator/Sponsor according to ICH, local 
regulations, or as specified in the Clinical Trial Agreement, whichever is longer; but at a 
minimum, all study documentation must be retained for 2 years after the last marketing 
application approval in an ICH region or after at least 2 years have elapsed since formal 
discontinuation of clinical development of ABI-009. 
Since the evaluations are not expected to benefit the patient directly or to alter the 
treatment course, the results of 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 
(e.g., 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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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1. 
Study Monitoring 
The Institution representative, 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, 
CRFs and other pertinent data) provided that patient confidentiality is respected. 
The Institution representative together with the AADi representative are responsible for 
verifying the CRFs as needed 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, CRFs, 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 CRFs, 
are resolved. 
13.2. 
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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14. 
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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15. 
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54. Cirstea D, Hideshima T, Rodig S, Santo L, Pozzi S, Vallet S, et al. Dual inhibition of 
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ICF_001.pdf: 
ABI-009/Nivolumab 
SOC-1701 Informed Consent 
Sarcoma Oncology Research Center 
 
 
 
 
 
 
Confidential and Proprietary 
Page 1 
ICF version 6.0: September 26, 2019 
 
 
RESEARCH SUBJECT INFORMED CONSENT FORM 
 
 
TITLE: 
A phase 1/2 single center investigation of safety/efficacy of 
nivolumab (Opdivo®) and ABI-009 (nab-rapamycin) in 
patients with advanced Ewing’s sarcoma, PEComa, 
epithelioid sarcoma, desmoid tumor, chordoma, non-small 
cell lung cancer, small cell lung cancer, urethelial carcinoma, 
melanoma, renal cell carcinoma, squamous cell carcinoma 
of head and neck, hepatocellular carcinoma, classical 
Hodgkin’s lymphoma, MSI-H/dMMR metastatic colorectal 
cancer, and tumors with genetic mutations sensitive to 
mTOR inhibitors. 
 
PROTOCOL NO.: 
SOC-1701 
 
 
 
PROTOCOL DATE: 
September 26, 2019 
 
SPONSOR: 
 Sarcoma Oncology Research Center 
 
INVESTIGATOR: 
Erlinda M. Gordon, MD 
 
2811 Wilshire Blvd., Suite 414 
Santa Monica, CA 90403 
USA 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Erlinda M. Gordon, MD 
 
310-825-6301 ID#11737 (24 hours) 
 
310-552-9999 
 
INFORMED CONSENT 
VERSION: 
6.0 
 
 
1. 
BACKGROUND AND PURPOSE 
 
A person who takes part in a research study is called a research or study subject. In this 
consent form “you” always refers to the research subject. If you are a legally authorized 
representative, please remember that “you” means the research (study) subject. 
 
You are being asked to take part in this study because you have been diagnosed with 
advanced Ewing’s sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, 
non-small cell lung cancer, small cell lung cancer, urethelial carcinoma, melanoma, 


ABI-009/Nivolumab 
SOC-1701 Informed Consent 
Sarcoma Oncology Research Center 
 
 
 
 
 
 
Confidential and Proprietary 
Page 2 
ICF version 6.0: September 26, 2019 
 
renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular 
carcinoma, classical Hodgkin’s lymphoma, MSI-H/dMMR metastatic colorectal cancer, 
and tumors with genetic mutations sensitive to mTOR inhibitors. 
 
The purpose of this study is to determine whether ABI-009 (study drug) in combination 
with nivolumab will make your cancer smaller and slow the spread of your cancer. 
About 40 patients will take part in this study. 
 
ABI-009, human albumin-bound rapamycin, is an experimental drug used to treat 
patients with five types of sarcoma in this study. Rapamycin, the active part of the drug, 
prevents a biological pathway out of control in sarcoma cancer cells. Rapamycin and 
similar types of drugs have been used in many other tumors, including advanced renal 
cell carcinoma. The human albumin component of ABI-009 may allow rapamycin to 
reach cancer cells more effectively. 
 
ABI-009 has not been approved for the treatment of advanced Ewing’s sarcoma, 
PEComa, epithelioid sarcoma, desmoid tumor, chordoma, non-small cell lung cancer, 
small cell lung cancer, urethelial carcinoma, melanoma, renal cell carcinoma, squamous 
cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin’s 
lymphoma, MSI-H/dMMR metastatic colorectal cancer, and tumors with genetic 
mutations sensitive to mTOR inhibitors. The information from this study might help us 
identify if ABI-009 plus nivolumab treatment is safe and effective in these diseases. 
 
This consent form gives you detailed information about this research study. If you wish 
to participate in the study, you will be asked to sign and date the informed consent form 
and you will be given a complete copy of this informed consent form to keep. 
 
2. 
WHAT DOES THE STUDY ENTAIL? 
 
This research study will be conducted at the Sarcoma Oncology Research Center by 
Dr. Erlinda M. Gordon, the Principal Investigator (person in charge of the study in this 
Cancer Center) and her study staff. About 40 patients will be entered in this study at this 
single site in the United States. 
 
Before you can receive study treatment, the doctor will perform tests to find out whether 
you can participate in the study. 
 
In this study, you will receive nivolumab (Opdivo, an FDA approved vaccine for lung 
cancer and a certain type of skin cancer, melanoma) given through a vein (intravenous) 
on Day 1, and ABI-009 also given through a vein once weekly on days 8 and 15 of a 
21-day cycle. ABI-009 will not be given in Cycle 1, and only nivolumab will be given. 
ABI-009 begin on day 8 of the second 3-week cycle. 
 
If you are found to be eligible by your study doctor, you will receive therapy within 14 
days. Treatment will last until your disease progresses or depending on how well you 
tolerate the therapy. After your study treatment has been completed, you will be 


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checked upon by phone calls every 3 months or more frequently if needed to see how 
you are doing and to collect information on any new anti-cancer treatment you may be 
taking. Altogether the total time you spend on study may be up to 1 year. Your study 
doctor or staff will tell you when and where you will go for treatment, tests, exams, and 
procedures. 
 


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The study doctor or his/her staff will perform the following procedures during the study: 
• At screening, a copy of your pathology report from your tumor sample will be 
collected. 
• At screening, your archived tumor will be tested for a genetic mutation known as 
PTEN 
• At screening, your demographic information (date of birth, sex, race, and 
ethnicity) will be collected. 
• At screening, you will be asked questions about past and present diseases, 
surgeries, allergies, medicines you are taking, other studies you were in, and any 
method of birth control, if appropriate. 
• At the beginning of every cycle and End of Treatment (EOT) visit, you will have a 
physical examination including medical/cancer history and measurement of vital 
signs (blood pressure, temperature, heart rate). 
• At screening, your height will be measured. 
•  At screening, day 1 and day 8 and day 15 of every cycle, your weight will be 
measured. 
• At screening, an electrocardiogram (or ECG) will be performed. This is a simple, 
painless test that records the heart electrical activity. 
• At screening, at day 1 of every cycle, and at the End of Treatment visit, your 
performance status will be assessed, which is your ability to carry out normal 
activities and take care of yourself. This will involve asking you questions about 
your daily life. 
• At screening, a urine sample will be collected for routine analysis. 
• At any time after signing the informed consent and up until 28 days after your last 
study treatment dose, you will be asked questions about any medical conditions 
or side effects which you may experience during the study 
• At screening and throughout the course of the study, you will be asked about 
additional medicines that you have taken (this includes medicines that you do not 
need a prescription for such as: aspirin, ibuprofen, vitamins, and herbal 
medicines) as well as additional procedures you underwent.  This includes 
medications taken less than or equal to28 days prior to screening. You should 
check with your study doctor before starting any new medicines. 
• If you are eligible to take part in the study, you will be asked to return to the clinic 
to receive your study treatments. If you are not eligible, the study staff will 
discuss other treatment options with you. 
• Blood samples will be taken: 
o If you are female and able to become pregnant, 5 mL (1 teaspoon) of 
blood will be drawn at screening and End of Treatment (EOT) visit for a 
serum pregnancy test to prove that you are not pregnant before your 
treatment begins and once treatment is completed. 
o At screening, the beginning of every cycle, and End of Treatment (EOT) 
visit, 5-10 mL (1-2 teaspoons) of blood will be collected to test for levels of 
certain common substances such as sodium, calcium, sugar, and others 
o At screening and at every study visit, 5 mL (1 teaspoon) will be collected 
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o At screening, about 5 mL (1 teaspoon) will be collected to test how well 
your blood clots 
o At screening and every 3 months, about 5 mL (1 teaspoon) will be 
collected to test your thyroid function 
o At screening, about 10 mL (2 teaspoons) will be collected to test for HIV, 
Hep B/C, and your liver functions. State/Provincial law requires positive 
test results for certain communicable diseases, including HIV, hepatitis, 
sexually transmitted infections, and tuberculosis, to be reported to a local 
health agency.  Some of the tests for this study must be reported when 
positive. The study doctor can discuss this with you. 
o At screening and every 3 months, about 5-10 mL (1-2 teaspoons) will be 
collected to test your fasting lipid (cholesterol test). You may be asked not 
to eat anything and only drink 9-12 hours before having your blood 
cholesterol tested 
o On the fifteenth day of the second and third cycles of ABI-009, 5 ml (1 
teaspoon) will be collected immediately before ABI-009 infusion, to 
determine the trough (lowest level) of rapamycin in your blood 
o After 3 courses of treatment, your study doctor may recommend that your 
tumor is removed and examined for the effects of the treatment on your 
tumor. 
•  Your study doctor will determine your response to treatment. This will be based 
on the information gathered from a CT scan or MRI scan of your chest, abdomen 
and pelvis within 14 days prior to first treatment, then every 6 weeks for the first 
year, and at the End of Treatment (EOT) visit only for those patients that 
discontinue treatment for a reason other than disease progression. Together, the 
total time you would have these scans during the study can be up to one year. 
NOTE: an unscheduled scan for suspected disease progression may occur at 
any time. If your disease recurs, no more CT or MRI scans will be done. CT scan 
uses a series of x-rays which create a three-dimensional picture of the inside of 
your body, while an MRI uses magnetic fields to create a picture. These scans 
allow the study doctor to measure if your cancer is progressing. 
• After your End of Treatment visit, you will be contacted every 3 months or more 
frequently if needed (can be by telephone) to see how you are doing and to 
collect information on any new treatments you may be taking. 
 
3. 
POTENTIAL BENEFITS OF THE STUDY 
 
There is no promise that the study treatment you receive in this study will help you. It is 
hoped that potential benefits may include improvement of some disease related 
symptoms and a decrease in the size of your tumor. You should be aware that the 
treatment you receive may be harmful. Information obtained from your participation may 
help other people in the future. 
 
4. 
POTENTIAL RISKS OF THE STUDY 
 


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Sometimes during a research study, new significant information becomes available 
about the treatment that is being studied. If this happens, your doctor will tell you about 
it and discuss with you whether you want to continue in the study. If you decide to 
withdraw, your doctor will make arrangements for your care to continue outside of the 
study. If you decide to continue with the study, you will be asked to sign an updated 
consent form that contains this new information. 
 
(a)  
Risks from the Study Procedures 
 
Risk with Intravenous (IV) Drug Administration:  Temporary irritation and bruising 
may occur at the infusion site.  There may also be discomfort, pain, or bruising from the 
needle puncture.  In rare cases, an infection may also occur at the site of the needle 
stick. 
 
Blood drawing - Needle sticks carry some risks such as fainting, bleeding, bruising, 
discomfort, dizziness, infection and/or pain at the puncture site. 
 
ECG: There are no serious risks with an ECG, it is a harmless and painless test that 
detects the heart’s electrical activity. They do not give off electrical charges, such as 
shocks. However, you may develop a mild rash where the electrodes (soft patches) 
were attached. These rashes often go away without treatment. 
 
CT and MRI Scans: 
 
As part of this study, you will have CT and MRI scans. CT scans involve exposure to 
radiation. Some people may be worried about the amount of radiation they receive 
during a CT scan. The amount of radiation from this entire study is well below the levels 
that are thought to result in a significant risk of harmful effects. Radiation exposure from 
a CT scan can be higher than from a regular x-ray. However, not having the procedure 
can be more risky than having it, especially if cancer is suspected. People considering 
having a CT scan must think about the risks and benefits. The amount of radiation 
exposure from having CT scans, in this study is about the same as the amount of 
radiation a person would get from natural surroundings in 3 years. 
 
You may get contrast (dye) for imaging. Some people experience mild itching or hives. 
Signs of a more serious allergic reaction include shortness of breath and swelling of the 
throat or other parts of the body, abdominal pain, or vomiting. You should tell the 
technologist immediately if you experience any of these symptoms, so you can be 
treated immediately. You may experience discomfort related to lying still in an enclosed 
space for a prolonged period of time while the CT scan or MRI is being taken. 
 
(b)  
Risks from the Study Treatment 
 
ABI-009 Risks  
 


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You may have side effects while you are in the study, but you will be carefully checked 
by the study doctor for any problems. There may be risks or side effects of the study 
drug that are unknown at this time. You should tell the study doctor/staff about anything 
that is bothering you or any side effect you have, even if you do not think they are 
related to the study drug. 
 
The following is a list of the most medically significant or most common side effects 
reported in previous studies and considered to be related to ABI-009. In some cases, 
side effects can be serious or long-lasting. Some side effects go away soon after you 
stop the study drug/therapy and some may take time to resolve. The study doctor may 
alter the dosage regimen of ABI-009 or give you medicines to help lessen the side 
effects. This is not a complete list of all side effects that may occur. For more 
information about risks and side effects, please ask the study doctor. 
 
Very common (10% or more chance that this will happen, based on a previous study 
with ABI-009): 
• low blood platelets (thrombocytopenia) 
• low blood hemoglobin (anemia) 
• low white blood cell count (neutropenia) 
• low potassium levels (hypokalemia) 
• low blood phosphate levels (hypophosphatemia) 
• diarrhea 
• nausea 
• constipation 
• inflammation of the mucus membrane (mucosal inflammation) 
• fatigue 
• decreased liver function (elevated AST) 
• weight decrease 
• rash 
• infection (candidiasis) 
• labored breathing (dyspnea) 
• lung inflammation (pneumonitis) 
 
Common (between a 4% to less than 10% chance that this will happen): 
• elevated potassium levels (hyperkalemia) 
• elevated lipid levels (hypertriglyceridemia) 
• irritations in the mouth (stomatitis) 
• vomiting 
• edema 
• cough 
• insomnia 
• weakness, numbness in hand and feet (neuropathy) 
 
Uncommon (between a 0.1 to less than 4% chance that this will happen): 
• decreased appetite 


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• anorexia 
• alkalosis 
• dehydration 
• elevated cholesterol (hypercholesterolemia) 
• elevated blood glucose (hyperglycemia) 
• elevated creatinine levels 
• low sodium levels (hyponatremia) 
• lip blister 
• oral pain 
• infusion site pain 
• fever 
• thirst 
• decreased liver function (elevated ALT) 
• low blood albumin levels 
• dermatitis 
• infections 
• vertigo 
• suicidal ideas 
• disorientations 
• fast heart rate (tachycardia) 
• hypertension 
• muscle pain (myalgia) 
• transient chest pain (acute coronary syndrome) 
 
ABI-009 contains human serum albumin. Human serum albumin presents a small risk of 
allergic or anaphylactic type reactions. Tell your doctor if you have ever had a reaction 
to human serum albumin. 
 


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Human serum albumin is a derivative of human blood. Based on effective donor 
screening and product manufacturing processes, it carries an extremely remote risk for 
transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a 
theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk 
actually exists, the risk of transmission would also be considered extremely remote. No 
cases of transmission of viral diseases, CJD, or vCJD have ever been identified for 
licensed albumin. 
 
Nivolumab Risks 
 
The following is a list of the most medically significant or most common side effects 
reported in previous studies and considered to be related to nivolumab. In some cases, 
side effects can be serious or long-lasting. Some side effects go away soon after you 
stop the study drug/therapy and some may take time to resolve. The study doctor may 
delay or permanently discontinue nivolumab or give you medicines to help lessen the 
side effects. This is not a complete list of all side effects that may occur. For more 
information about risks and side effects, please ask the study doctor. 
 
Very common (10% or more chance that this will happen, based on previous studies 
with nivolumab): 
• Rash 
• Itchiness 
• Cough and congested throat 
• Edema or swelling of legs and feet 
• Decreased liver function (Increased AST, ALT, alkaline phosphatase 
• Decreased blood electrolytes (decreased sodium, potassium) 
 
Special immune side effects: 
• lung inflammation (pneumonitis) 3.4% 
• diarrhea (colitis) 
21% 
• liver disease (hepatitis) 
9-28% 
• kidney disease (nephritis) 13% 
• thyroid disorders (hypo- or hyperthyroidism) 
2-8% 
 
Uncommon (2% or less that this will happen, based on previous studies with nivolumab 
• Pancreatitis 
• Increased amylase 
• Increased lipase 
• Eye disorders (uveitis, iridocyclitis) 
• Facial weakness 
• Dizziness 
• Irregular heart rate (ventricular arrhythmia) 
• Disorders of the nervous system (demyelination, neuropathy, hypophysitis; 
Guillain-Barre syndrome; muscle weakness) 
• Disorders of Adrenal gland (adrenal insufficiency) 


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• Diabetic ketoacidosis 
 
General Disorders and Administration Site Conditions: infusion-related reactions can 
happen. Dexamethasone is given to prevent allergic reactions. Dexamethasone may 
cause irritability, increased appetite, stomach bleeding, stomach ache, and rarely, 
confusion. You will receive an antacid to prevent stomach ache and stomach bleeding 
as a result of dexamethasone treatment. 
 
Pregnancy Risk with ABI-009 
 
No studies of ABI-009 have been conducted in pregnancy. It is not known if ABI-009 
passes into milk during breast feeding 
 
Females:  If you decide to take part in this study, and are able to have children, you 
must agree to use medical doctor-approved contraception throughout the study, and for 
3 months after your last dose of study treatment. In addition, if you have had your tubes 
tied (tubal ligation) you must also agree to use a second form of birth control. If you 
become pregnant while receiving study treatment you must tell the study doctor right 
away. If this happens, your participation in this study treatment will be discontinued.  If 
you become pregnant within 3 months after taking your last dose of study drug you 
must tell the study doctor right away. The study doctor will follow you and your 
pregnancy to birth. 
 
Males: If you are a man, you will not be able to donate sperm for the length of the trial 
and for 3 months following treatment. If you have a partner able to have children, you 
must agree to use a medical doctor-approved form of contraception throughout the 
study, and should avoid fathering a child for 3 months after your last dose of study 
treatment. In addition, if you have had a vasectomy you must also agree to use a 
second form of birth control. If your partner becomes pregnant during the study or within 
3 months after you took your last dose of study treatment, you must tell the study doctor 
right away. Your study doctor and the sponsor will ask your partner to allow them to 
collect information about her pregnancy and the health of the baby in a separate 
consent form. 
 


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5. 
OTHER CHOICES 
 
You do not have to take part in this study in order to receive treatment for your cancer. 
Although you have failed standard treatment, there may be other drugs which your 
doctor can prescribe without being on the study. Your doctor will inform you of these 
other options. 
 
6. 
VOLUNTARY PARTICIPATION IN THE STUDY 
 
Your participation in this study is voluntary. You can decide not to take part, or leave the 
study at any time for any reason without penalty or loss of medical care or benefits to 
which you are entitled. 
 
If you wish to stop the study treatment, please tell the study doctor or his/her staff and 
return to the study center for a final visit. If you want to stop the study treatment 
because of a side effect, it is important that you tell the study doctor about the side 
effect. The study doctor will help you stop safely and make arrangements for further 
medical care and follow-up. 
 
7. 
WHAT ARE MY RESPONSIBILITIES WHILE PARTICIPATING IN 
THE STUDY? 
 
• Follow the instructions of the study doctor or the study staff. 
• Tell the study doctor or his/her staff about any injuries or illness (including side 
effects, discomfort, or declining health) you may experience in the course of the 
study. 
• If you visit or receive medical care from another doctor, tell him/her that you are 
in a research study. 
• Talk to the study doctor before you take any new medicines, even if another 
doctor prescribed the medicines.  If there is an emergency, you may take the 
medicines and then tell the study doctor as soon as possible. 
• Do not participate in any other medical research study while you are on this 
study, until you have discussed it with the study doctor. 
• Do not miss your appointments with the study doctor or his/her staff. 
 
8. 
YOUR PARTICIPATION IN THE STUDY MAY BE STOPPED 
 
The study doctor may stop your participation if you do not follow the instructions in 
Section 7. He/she may also stop your participation, if you have side effects, if your 
condition worsens, if you or your partner become pregnant, or you no longer meet the 
requirements of the study. 
 
The Sarcoma Oncology Research Center or the drug manufacturer, AADi, may also 
stop your participation or the study at any time (for example, for safety reasons). If that 
happens, the reason will be explained to you. 


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If the study doctor or AADi stops your study participation, the study doctor will make 
arrangements for further medical care and follow-up. 
 
9. 
NEW INFORMATION ABOUT THE STUDY TREATMENT 
 
During the course of a study, new information may become available that may influence 
your willingness to participate in the study. If that happens, the study doctor will tell you 
about it. 
 
10. 
PRIVACY AND CONFIDENTIALITY 
 
10.1. 
Data privacy 
 
The study doctor will collect information from you. 
 
All the information will be processed without your name, ID number or any other 
information which allows your identification. The information will be labeled with a code. 
A confidential list of names will link the code to your name. Only authorized people (for 
example, the study doctor) will have access to the list of names and be able to identify 
you. 
 
The study doctor will keep your medical records and any other record identifying you 
confidential. To the extent permitted by law, monitors, auditors, the Food and Drug 
Administration and other competent authorities will have access to your medical records 
in order to verify the study data and compliance with the study procedures. Those 
persons will have the obligation to keep your records and the information contained in 
them confidential. 
 
The study results may be mentioned in medical books or journals or used for teaching 
purposes. Your identity will not be mentioned. The Sarcoma Oncology Center and AADi 
may also share information collected during the study with scientists outside Sarcoma 
Oncology Center and AADi for further scientific research in the interest of public health. 
The Sarcoma Oncology Center and AADi will, however, not provide information about 
your identity to these scientists. 
 
If you leave the study or after your participation has been stopped for any other reason 
(see Section 8 above) any information collected while you were in the study will be kept 
and may be included in the final results of the study. 
 
You have the right to access and verify your personal information held by the Sarcoma 
Research Oncology Center and AADi and to obtain its deletion or the correction if it is 
inaccurate. If you wish to exercise that right please tell the study doctor (see contact 
details above). 
 


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11. 
WILL YOU BE PAID FOR YOUR PARTICIPATION IN THE 
STUDY? 
 
You will not receive payment for being in the study. Please discuss with the research 
staff what will be reimbursed and what information you should provide. 
 
Taking part in this study does not make you an employee of the sponsor or the study 
site. 
 
12. 
COSTS FOR BEING IN THE STUDY 
 
The collaborating company of this study, AADi, will provide the AABI-009 study drugs to 
you free of charge. The nivolumab drug is FDA-approved and will be charged to your 
insurance company or provided free of charge by the drug manufacturer, Bristol Myers 
Squibb. Costs related to your routine medical care will be billed to you or your insurance 
company. This is because they are the same standard of care you would receive if you 
were not on study. Your health insurance company may or may not pay for these 
charges. 
 
13. 
STUDY RELATED INJURIES 
 
You should notify the study doctor as soon as you believe you have had a study-related 
illness or injury, so that proper medical care can be provided. You will receive proper 
medical care if you are injured or become ill in connection with the study. If the injury or 
illness is directly related to the proper management of the study drug or proper 
performance of research procedures, AADi will pay the reasonable costs of that 
treatment to the extent those costs were necessary, directly related to the Study and are 
not covered by your health insurance. If your insurance does not cover an expense and 
AADi does not pay for the medical expense, you may be responsible for payment. 
 


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However, AADi will not pay for expenses that are (in any way) related to your failure to 
follow instructions, the progression of any illness or disease you may currently have or 
the wrongdoing on the part of the study site, study doctor, or study staff. Further, AADi 
will not routinely pay for lost wages or other damages. 
 
14. 
WAIVER OF RIGHTS TO DISCOVERIES 
 
You agree that you will not receive any rights to or compensation for any discovery, 
development, invention, or patent that may result from your participation in this study. 
 
15. 
IF YOU NEED MORE INFORMATION 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
ClinicalTrials.gov is a registry in English of federally and privately supported clinical 
trials conducted in the United States and around the world. ClinicalTrials.gov gives you 
information about a trial's purpose, who may participate, locations, and contact 
information for more details. 
 
When the results of the study are available, you will be given an opportunity to receive 
them. 
 
Please do not hesitate to contact the study doctor if you have any questions, concerns, 
or complaints about the study, the procedures, the treatment, or your rights, if you need 
help because you suffered an injury or illness in the course of the study, or if you want 
to review your personal data held by the study doctor. The contact details of the study 
doctor are mentioned at the top of this document. 
 
If you have questions about your rights while you are in this study or if you have 
concerns, or complaints about the research, you can contact the IRB. Western 
Institutional Review Board® (WIRB®) 1019 39th Avenue SE Suite 120, Puyallup 
Washington 98374-2115, Telephone: 1-800-562-4789 or 360-252-2500, E-mail: 
Help@wirb.com. The IRB/IEC is a self-governing group of people who review research 
studies to make sure the safety and rights of the people taking part in the study are 
protected. The IRB/IEC for this study is Western IRB and they have given their approval 
or favorable opinion for this study to begin.  They will continue to review the study while 
it is going on. 
 
WIRB will not be able to answer some study-specific questions, such as questions 
about appointment times.  However, you may contact WIRB if the research staff cannot 
be reached or if you wish to talk to someone other than the research staff. 
 
 


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INFORMED CONSENT 
 
Feel free to discuss the information in this document with your family, doctor(s) or 
friends. Do not sign this document until you have had a chance to ask the study doctor 
or his/her staff all of your questions and all questions have been answered to your 
satisfaction. 
• I agree to participate in the study. 
• I understand that I can leave the study at any time. 
• I understand and agree that study monitors, auditors, the ethics committee, the 
Food and Drug Administration, and other competent authorities will have direct 
access to my medical records in order to verify the study data and compliance 
with the study procedures. 
• I agree that my personal data are collected for the purposes of the study and the 
follow-up of the safety of the study medication. If my participation stops, my 
personal data may be further processed and the samples which I provided during 
the study will be analyzed for the purposes of the study and to follow-up the 
safety and the effect of the study drug. AADi may share information collected 
during the study with scientists outside AADi for further scientific research in the 
interest of public health. AADi shall however not share information about my 
identity with these scientists. 
• I agree /I do not agree (circle one) that my family doctor can be informed that I 
am taking part in the study. 
• If I pass away after I leave the study, I authorize/I do not authorize (circle one): 
(a) the study doctor or the doctor in charge of my treatment to inform AADi 
about the date and the cause of my death; and  
(b) AADi to process this information for the purposes of the study or the follow-
up of the safety and the effect of the study drug. 
 
I understand that all medical information, specimens, imaging studies and 
samples obtained from me during this study will be used and kept by Sarcoma 
Oncology Research Center/AADi for the purposes described in this Informed 
Consent Form. I also understand that all data and materials created from this 
study shall become the property of Sarcoma Oncology Research Center and 
AADi. I further understand that Sarcoma Oncology Center and AADi have no 
plans to compensate (pay) me or to share in any possible profits that Sarcoma 
Oncology Research Center and AADi may derive (collect) from such specimens, 
samples, data, or materials. 
 
I have read this Informed Consent Form, which is written in a language I understand, 
and I understand it. I understand the procedures and what I will be asked to do. All my 
questions about the study, possible risks, side effects and study drug have been 
answered. I understand that I can choose not to take part in this study without penalty or 
loss of rights to which I am entitled. I have been told that I can change my mind about 
being in the study at any time and that by signing this consent form, I am not giving up 
any of my legal rights. I have told the person obtaining this consent if I am involved in 


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other medical research studies. I have been given a copy of this Informed Consent 
Form and a copy of the California Research Participant's Bill of Rights. 
 
Signature 
 
By signing this information and consent form, you have not given up any legal rights 
which you otherwise would have as a research participant. 
 
 
 
 
Research Subject’s Name (Print) 
 
 
 
 
 
 
Research Subject’s Signature 
Date of signature 
 
I have explained the purpose of this study, the study procedures, the possible risks, 
discomforts and benefits. I have answered all questions regarding the study to the best 
of my ability. 


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CONFIDENTIALITY 
 
Records identifying your medical information will be kept confidential to the 
extent permitted by applicable laws and/or regulations, and will not be 
made publicly available. If the results of the study are published, your 
identity will remain confidential. Your name will not be used in any study 
reports, blood samples, or scans, and all study reports will be used for 
research purposes only. The Sarcoma Oncology Research Center and 
AADi, its designee(s), ethics committees, independent review boards, 
personnel at the study site, and various government health agencies (such 
as the Food and Drug Administration) may inspect and review your medical 
records of this study for the purpose of checking data collected for the 
study. By signing this consent, you are authorizing access to your medical 
records for the purpose of checking data collected from your participation in 
this study. 
 
You also provide consent for the release of copies of your CT/MRI scans, 
laboratory test results, and all medical reports for review as part of this 
research study. To protect your privacy, your blood and tissue samples and 
scans will be labeled with only your subject ID as an identifier. There will be 
no personal identifiers to link these samples to you. Samples and scans 
may be transferred to companies working with the Sponsor for testing or 
review for this study. Although efforts will be made to protect your privacy, 
absolute confidentiality of your records cannot be guaranteed. 
 
You are also giving your permission to have your Protected Health 
Information (PHI) collected, used and disclosed for the purposes of this 
clinical trial. PHI is protected by federal privacy laws, but once the study 
doctor discloses it to others, it could be redisclosed and will no longer be 
protected by the federal privacy laws. 
 


ABI-009/Nivolumab 
SOC-1701 Informed Consent 
Sarcoma Oncology Research Center 
 
 
 
 
 
 
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You may decide not to give permission for the use or disclosure of your PHI 
for this study; however, you will not be able to participate in the study. This 
is because the study doctor and site staff would not be able to collect all the 
information that is needed. You may also cancel your permission to use or 
disclose PHI after you have started the study; however, you will not be able 
to continue participating in the study or receive study drug. This is because 
the study doctor and site staff would not be able to continue collecting all 
the information that is needed for the study. 
 
If you choose to withdraw your authorization to use and disclose your 
personal health information, please notify the study doctor in writing. 
 
Signing this informed consent also allows the study doctor to release study 
results to the Sponsor and its designees. The study results will not contain 
information that identifies you (such as your name). 
 
This permission will be good until December 31, 2060. 
 
Your study doctor will keep your personal medical records and a list that 
links each patient’s name to his or her study subject number for at least 15 
years. 
 
After your PHI is disclosed to the study sponsor, the results of the study 
may be reanalyzed at a later date and may be combined with the results of 
other studies. The study collaborator (AADi, LLC) and people who work 
with the study sponsor may use your coded study information, samples and 
scans for this study and for other research purposes in the future, including: 
• Reviewing the safety and effectiveness of ABI-009/nivolumab 
• Conducting performance reviews of the study 
• Improving the design of future studies 
• Studying UPS, LPS other solid tumors associated with this study, as 
well as any related diseases 
 


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SOC-1701 Informed Consent 
Sarcoma Oncology Research Center 
 
 
 
 
 
 
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You have the right to request access to, and to correct any inaccuracies in 
your recorded PHI collected as part of this study. However, due to the 
nature of the study it may only be possible to access this information after 
the study is completed. This is done to maintain the scientific integrity of the 
study. After the study is concluded you can obtain access to your 
information through your study doctor. 
 
As your primary doctor may not be the doctor you will be seeing for this 
study, you should inform him/her of your participation in this study. The 
study doctor may contact your primary doctor to obtain medical records. 
 
 
 
 
Research Subject’s Name (Print) 
 
 
 
 
 
 
Research Subject’s Signature 
Date of signature 
 
 
 
 
Name of Person Obtaining Consent (print) 
 
 
 
 
 
 
Signature of Person Obtaining Consent 
Date of signature 
 
 
 


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SOC-1701 Informed Consent 
Sarcoma Oncology Research Center 
 
 
 
 
 
 
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ASSENT SIGNATURES, For Subjects Ages 12 through 17 years: 
 
Assent: 
This research study has been explained to me and I agree to be in this 
study. 
_____________________________________             ________________        
Subject’s Signature for Assent 
Date Age (years) 
 
I confirm that I have explained the study to the extent compatible with the 
subject’s understanding, and that the subject has agreed to be in the study. 
 
____________________________________________     _____________ 
Signature of Person Conducting Assent Discussion  
Date 
 
 
---------------------------------- Use the following only if applicable ------------------  
 
If this consent form is read to the subject because the subject is unable to 
read the form, an impartial witness not affiliated with the research or 
investigator must be present for the consent and sign the following 
statement: 
 
I confirm that the information in the consent form and any other written 
information was accurately explained to, and apparently understood by, the 
subject.  The subject freely consented to be in the research study. 
 
 
___________________________ ______ 
 
 
 
Impartial Witnesses Signature 
Date  
 
 
___________________________ 
PRINT Name of Impartial Witness 
 
Note:  This signature block cannot be used for translations into another 
language.  A translated consent form is necessary for enrolling subjects 
who do not speak English.