Clinical trial NCT03439462
Conditions: Colorectal Cancer Metastatic
Sponsor: Aadi Bioscience, Inc.
Start date: 2018-07-01; Completion date: 2022-08-26
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A phase 1/2 multi-center investigation of nab-sirolimus (also known as ABI-009, nab-rapamycin) in combination with mFOLFOX6 and Bevacizumab as first-line therapy in patients with metastatic colorectal cancer

Detailed description:
This study is a prospective phase 1/2, single arm, open-label, multi-institutional study to identify the RP2D and determine the efficacy and safety profile of nab-sirolimus administered as first-line therapy in combination with mFOLFOX6 and bevacizumab in patients with metastatic colorectal cancer.

Arms: arm 1: Single arm, open-label, multi-institutional study to identify the RP2D and determine the efficacy and safety profile of nab-sirolimus administered as first-line therapy in combination with mFOLFOX6 and bevacizumab in patients with metastatic CRC.
Interventions: intervention 1: nab-sirolimus
Intervention descriptions: intervention 1: nab-sirolimus combined with mFOLFOX6 + bevacizumab

Protocol documents:
Prot_SAP_000.pdf: 
Cover Page 
 
Study COLO-007, NCT# 03439462 
 
 
Protocol including Statistical Analysis Plan 
 
Last Approved Version & Date: Amendment V2.1, 05-Sep-2019 
 
 
 
Protocol Title: 
A phase 1/2 multi-center investigation of ABI-009  
(nab-sirolimus) in combination with FOLFOX and 
bevacizumab as first-line therapy in patients with advanced 
or metastatic colorectal cancer 




ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                 Aadi Bioscience 
Confidential and Proprietary 
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Amendment 2.1 
 
 
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
 
 
 
 
 
 
 
 
 






ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                 Aadi Bioscience 
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PROTOCOL SYNOPSIS 
INVESTIGATIONAL 
PRODUCT 
ABI-009, sirolimus albumin-bound nanoparticles for injectable 
suspension, nab-sirolimus, formerly nab-rapamycin 
TITLE 
A phase 1/2 multi-center investigation of ABI-009 (nab-sirolimus) in 
combination with mFOLFOX6 and Bevacizumab as first-line therapy 
in patients with advanced or metastatic colorectal cancer 
PROTOCOL 
NUMBER 
COLO-007 
PHASE  
Phase 1/2 
STUDY 
OBJECTIVES 
Objectives in Phase 1 
Primary 
• To identify the recommended phase 2 dose (RP2D) and 
schedule of ABI-009 in combination with mFOLFOX6 and 
bevacizumab 
Secondary 
• To evaluate the safety and preliminary efficacy of ABI-009 in 
combination with mFOLFOX6 and bevacizumab at the RP2D 
 
Objectives in Phase 2 
Primary 
• To evaluate the efficacy of ABI-009 in combination with 
mFOLFOX6 and bevacizumab at the RP2D for all patients as 
well as based on PTEN status 
Secondary 
• To evaluate the safety and toxicity profile of ABI-009 in 
combination with mFOLFOX6 and bevacizumab at the RP2D 
Exploratory 
• To identify predictive molecular biomarkers for patients treated 
with 
ABI-009 
in 
combination 
with 
mFOLFOX6 
and 
bevacizumab 
STUDY 
ENDPOINTS 
Endpoints in Phase 1 
Primary Endpoint  
• Dose-limiting-toxicities (DLTs) and maximum-tolerated dose 
(MTD) of ABI-009 in combination with mFOLFOX6 and 
bevacizumab 
Secondary endpoint 
• Safety profile of dose cohorts analyzed separately and together 
• Disease control rate (DCR) assessed by investigators, dose 
cohorts analyzed separately and together 
Endpoints in Phase 2 – data both from phase 1 and 2  
Primary Endpoint  
• Progression-free (PF) rate at 6 months  
Secondary endpoints 


ABI-009/mFOLFOX6/Bev 
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• Median progression-free survival (PFS), overall response rate 
(ORR), duration of response (DOR), and DCR for all patients 
and based on PTEN status 
• PF rate at 6 months based on PTEN status 
• Safety at RP2D 
Exploratory Endpoints  
• Biomarkers: 
o Pre-treatment metastatic tumor biopsy: (fresh or 
archival) are required from all patients to assess 
baseline biomarker and mutational analysis, including 
PTEN loss evaluation, PIK3CA and Ras mutational 
status, and mTOR pathway markers (including, but not 
limited to S6K, 4EBP1). In particular, PIK3CA mutations 
and PTEN loss will be analyzed by IHC to evaluate as 
potential predictive biomarkers of response to mTOR 
inhibition. If tissue from metastatic site is not available, 
primary lesion tissue is acceptable. Reports on 
mutational status will be collected from all patients, if 
available. 
o Blood samples: for cell-free plasma DNA collection 
(pretreatment, C3 and C6 D1 post-treatment, upon 
disease progression, and/or end of last dose of 
treatment) for all patients. Molecular analysis of 
circulating DNA assay using next generation sequencing 
to assess changes over time as response to therapy of 
the prevalence of mutations identified in the baseline 
tumor samples 
 Nucleic acids extracted from blood can also be 
used to investigate whether circulating tumor 
nucleic acids are associated with disease 
progression  
STUDY DESIGN 
and DOSE-
FINDING RULES 
This study is a prospective phase 1/2, single arm, open-label, multi-
institutional study to identify the RP2D and determine the efficacy and 
safety profile of ABI-009 administered as first-line therapy in 
combination with mFOLFOX6 and bevacizumab in patients with 
advanced or metastatic colorectal cancer. A cycle will consist of 28 
days. 
The study will be conducted in compliance with International 
Conference on Harmonisation (ICH) Good Clinical Practices (GCPs). 
In the dose-finding portion of the study (phase 1), dose levels of ABI-
009 will be tested in cohorts of 3 patients each using the 3+3 dose-
finding design, with the starting dose of 20 mg/m2 given once every 2 
week on Days 1 and 15 in a 28-day cycle.  
 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                 Aadi Bioscience 
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Dose Levels 
ABI-009 in mg/m2 
IV every 2 week 
-2 
10 
-1 
15 
1 
20 
2 
30 
3 
45 
Escalation to the next dose level with a new cohort of 3 patients will 
occur after no DLT was observed in the first 1 cycle (28 days). There 
will be no intra-patient dose escalation allowed. If a DLT occurs in a 
cohort, additional 3 patients will be recruited to the cohort. If no further 
DLTs occur, then a new cohort of 3 patients at the next higher dose 
level can be enrolled. If 2/6 patients at dose level 1 experience a DLT, 
then that cohort will be closed to further enrollment and 3 patients will 
be enrolled at the next lower dose level, and so on. The MTD is the 
highest dose level in which ≤1 patient has a DLT. The RP2D is 
identified based of the totality of safety and efficacy data. 
The original schedule of ABI-009 given weekly for 3 weeks followed by 
a week of rest (qw3/4) has been changed to every 2 weeks with 
Amendment 2, to align with the dosing schedule of the standard of 
care, FOLFOX + bevacizumab. Patients receiving ABI-009 qw3/4, the 
original dosing schedule, will drop Day 8 ABI-009 and switch to the 
every-2-week schedule. 
Once the dose-finding portion of the study is concluded and RP2D is 
identified, patients receiving a lower dose may be allowed to receive 
ABI-009 at the RP2D, based on the investigator judgment and 
discussion with the medical monitor. 
NUMBER OF 
PATIENTS 
Up to 55 evaluable patients will be enrolled in this phase 1/2 study, 
with up to 18 patients in the dose-finding phase 1 portion, and 34-37 
additional patients in phase 2 (total N = 40 in phase 2, including 
patients from phase 1 at the RP2D).  
SAMPLE SIZE 
ESTIMATE 
In phase 1, it is estimated that a maximum of 18 patients will be 
required to achieve the MTD; however, MTD could be reached with as 
few as 5 patients.  
In phase 2, 34-37 additional eligible patients will be enrolled at the 
RP2D, for a total of 40 evaluable patients (including 3-6 patients from 
phase 1 at the RP2D). Assuming a 10% attrition rate, at least 44 
patients would need to be enrolled for the phase 2 portion of the study. 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007        
 Aadi Bioscience 
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The focus of the phase 2 portion of the study will be on the estimation 
of the magnitude of treatment effect, as measured by PF rate at 6 
months. Based on an assumed 6-month PF rate of 90% and a sample 
size of 40 patients, the 95% confidence intervals for the 6-month PF 
rate will be 76.3% to 97.2%. 
INCLUSION 
CRITERIA 
A patient will be eligible for inclusion in this study only if all of the 
following criteria are met at screening: 
1. Patients with histologically confirmed advanced or metastatic
colorectal cancers for whom chemotherapy is indicated. If biopsy
from metastatic site is not feasible, imaging may be used to confirm
the presence of metastasis in a patient that is already previously
histologically confirmed for colorectal cancer.
2. Patients must not have had prior chemotherapy for advanced or
metastatic disease. Patients could have received adjuvant
chemotherapy or adjuvant chemo-radiotherapy.
3. Patients must have at least 1 measurable site of disease according
to RECIST v1.1 that has not been previously irradiated. If the
patient has had previous radiation to the marker lesion(s), there
must be radiological evidence of progression since the radiation.
4. Eligible patients, 18 years or older, with Eastern Cooperative
Oncology Group (ECOG) performance status 0, 1, or 2.
5. Patients must not have been previously treated with an mTOR
inhibitor.
6. Adequate liver function:
a. Total bilirubin ≤1.5 x upper limit of normal (ULN) mg/dL (except
in the dose escalation phase, in which total bilirubin is <ULN)
b. Aspartate 
aminotransferase 
(AST) 
and 
alanine
aminotransferase (ALT) ≤2.5 x ULN (<5 x ULN if the patient has
liver metastases).
7. Adequate renal function:
a. Serum creatinine ≤2 x ULN or creatinine clearance >50 cc/hr 
(Cockcroft-Gault).
8. Adequate biological parameters:
a. Absolute neutrophil count (ANC) ≥1.5 × 109/L
b. Platelet count ≥100,000/mm3 (100 × 109/L)
c. Hemoglobin ≥9 g/dL.
9. Fasting serum triglyceride ≤300 mg/dL; fasting serum cholesterol 
≤350 mg/dL.
10. INR and PTT <1.5 x ULN (anticoagulation is allowed if target INR 
<1.5 on a stable dose of warfarin or on a stable dose of LMW 
heparin for >2 weeks at time of enrollment).
11. M inimum of 4 weeks since any major surgery, completion of 
radiation, or completion of all prior systemic anticancer therapy, 
and ≥6 months since adjuvant FOLFOX therapy (adequately 
recovered from the acute toxicities of any prior therapy, including 
neuropathy should be grade ≤1).


ABI-009/mFOLFOX6/Bev 
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12. 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 throughout 3 months after last dose of IP 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 
and throughout 3 months after last dose of IP. A second form of 
birth control is required even if he has undergone a successful 
vasectomy. 
13. Life expectancy of >3 months, as determined by the investigator. 
14. Ability to understand and sign informed consent. 
15. 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. History 
of 
severe 
and 
uncontrolled 
allergic 
reactions 
to 
bevacizumab 
2. Prior treatment with FOLFOX or bevacizumab within the preceding 
4 weeks 
3. Patients currently receiving or have received anticancer therapies 
within 4 weeks of the start of study treatment (including 
chemotherapy, radiation therapy, antibody-based therapy, etc.) 
4. Patients, who have had a major surgery or significant traumatic 
injury within 4 weeks of start of study drug, patients who have not 
recovered from the side effects of any major surgery (defined as 
requiring general anesthesia) or patients that may require major 
surgery during the course of the study 
5. Chronic 
treatment 
with 
systemic 
steroids 
or 
another 
immunosuppressive agent; topical or inhaled corticosteroids are 
allowed 
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. Patients who have any severe and/or uncontrolled medical or 
psychiatric conditions or other conditions that could affect their 
participation including: 
a. 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 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                 Aadi Bioscience 
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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. 
b. Unstable angina pectoris, symptomatic congestive heart failure, 
myocardial infarction ≤6 months prior to first study treatment, 
serious uncontrolled cardiac arrhythmia or any other clinically 
significant cardiac disease 
c. Pre-existing severely impaired lung function as defined as 
spirometry and DLCO that is 50% of the normal predicted value 
and/or O2 saturation that is 88% or less at rest on room air (Note: 
spirometry and PFTs not required to be performed unless 
clinically indicated). 
d. Uncontrolled diabetes as defined by fasting serum glucose >1.5x 
ULN or by HbA1c >8% despite adequate therapy. 
e. Any active (acute or chronic) or uncontrolled infection/ disorders.  
f. Nonmalignant medical illnesses that are uncontrolled or whose 
control may be jeopardized by the treatment with the study 
therapy. 
Note, 
controlled 
non-melanoma 
skin 
cancers, 
carcinoma in situ of the cervix, resected incidental prostate 
cancer, or other adequately treated carcinoma-in-situ may be 
eligible, after documented discussion with the sponsor / medical 
monitor. 
g. Known liver disease such as cirrhosis or severe hepatic 
impairment (Child-Pugh class C). 
h.   Uncontrolled hypertension (systolic blood pressure ≥160 mm Hg 
and/or diastolic blood pressure ≥90 mm Hg. 
8. Patients with history of interstitial lung disease and/or pneumonitis, 
or pulmonary hypertension. 
9.   Patients with history of intestinal perforations, fistula, hemorrhages 
and/or hemoptysis ≤6 months prior to first study treatment. 
10. A known history of HIV seropositivity. 
11. Active Hepatitis B or Hepatitis C. Note: A detailed assessment of 
Hepatitis B/C medical history and risk factors must be done at 
screening for all patients.  HBV DNA and HCV RNA PCR testing are 
required at screening for all patients with a positive medical history 
based on risk factors and/or confirmation of prior HBV/HCV 
infection. 
12. Patients with an active bleeding diathesis or on oral anti-vitamin K 
medication (except low dose warfarin [Coumadin] or heparin). 
13. 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. 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                 Aadi Bioscience 
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DURATION OF 
TREATMENT AND 
STUDY 
PARTICIPATION  
The study is expected to take approximately 24 months from first 
patient enrolled to last patient follow-up, including approximately 12 
months of enrollment period, an estimated 12 months of treatment (or 
until treatment is no longer tolerated).   
End of Treatment (EOT) for a patient is defined as the date of the last 
dose of ABI-009. End of Treatment Visit for a patient is when safety 
assessments and procedures are performed after the last treatment, 
which must occur within 1 month after the last dose of ABI-009.   
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.  
Follow-up period begins 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 of new 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. 
STUDY DRUG 
ADMINISTRATION 
With Amendment 2, the starting dose and schedule of ABI-009 is 20 
mg/m2 given every-2-weeks (28-day cycle) by IV infusion over 30 
minutes (+10 mins window allowed, ie 30-40 mins infusion). 
Bevacizumab and mFOLFOX6 will be administered every 2 weeks, 
starting Cycle 1, Day 1.  
Modified FOLFOX6 regimen: Oxaliplatin 85 mg/m2 IV with LV 400 
mg/m2 IV over 2 hours plus 5FU 400 mg/m2 IV bolus and 2,400 mg/m2 
continuous infusion over 46 hours every 2 weeks. Dose modifications 
of each agent in FOLFOX may be made independently based on the 
specific types of toxicities observed. Bevacizumab may be skipped or 
discontinued for bevacizumab-related toxicities, but the dose is not 
reduced. 
Patients will continue to therapy until disease progression, 
unacceptable toxicity, until in the opinion of the investigator the 
patient is no longer benefiting from therapy, or at the patient’s 
discretion. Patients who remain on treatment for more than 6 months 
may be switched to mFOLFOX and bevacizumab every 3 weeks and 
ABI-009 given weekly for 2 weeks followed by a week of rest (qw2/3, 
21-day cycle) at the discretion of the investigator. Single agent ABI-
009 may be continued if mFOLFOX6 and/or bevacizumab are 
discontinued due to toxicity or achievement of maximum benefit in 
the opinion of the investigator and approval of the medical monitor 
and sponsor. 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                 Aadi Bioscience 
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KEY EFFICACY 
ASSESSMENTS 
Efficacy will be assessed by investigators using CT / PET scans and 
RECIST v1.1. Only RECIST v1.1 criteria will be used to assess 
response; PET will be used for qualitative purposes only. 
For the phase 2 portion of the study the primary endpoint is PF rate 
at 6 months. Progression-free rate at 6 months is the proportion of 
patients who are progression-free and alive at 6 months. The point 
estimate of the PF rate and the exact two-sided 95% confidence 
interval will be provided.  
Progression-free survival is defined as the time from the first day of 
study drug administration to disease progression or death due to any 
cause. For PFS, the KM estimates and corresponding two-sided 95% 
confidence intervals for the median and quartiles will be provided. 
The KM plot may also be provided. 
The ORR and DCR will be reported along with exact 95% confidence 
intervals computed by the Clopper-Pearson method. Additionally, all 
efficacy endpoints will also be analyzed based on PTEN status. 
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) v5.0. 
Physical examination, vital signs, laboratory assessments (eg, serum 
chemistry, hematology), and ECOG performance status will be 
monitored. All serious AEs (regardless of relationship to IP) will be 
followed until resolution. Local laboratory analysis will be performed 
as per study schedule. 
 










ABI-009/mFOLFOX6/Bev 
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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 
CEA 
CI 
carcinoembryonic antigen 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DCR 
DOR 
disease control rate 
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
Immunohistochemistry 


ABI-009/mFOLFOX6/Bev 
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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 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PF rate 
PFS 
Progression-free rate 
Progression-free survival 
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 
upper limit of normal 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
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Term 
Definition/Explanation 
Study Day 1 
First day that protocol-specified IP is administered to the 
patient. 
End of Treatment 
The date of the last dose of ABI-009 or mFOLFOX6/bev for an 
individual patient, whichever is later. 
End of Treatment 
Visit 
For a patient is when safety assessments and procedures are 
performed after the last treatment, which should occur within 1 
week (±3 days) after the last dose of ABI-009 or 
mFOLFOX6/bev, whichever is later.  
Follow-up Period 
 
The 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 initiation of new 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. 
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.  
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. 
Efficacy Analysis 
Dataset  
 
All enrolled patients with measurable tumor per RECIST v1.1 
at baseline who received at least 2 doses of ABI-009 and had 
a follow-up CT / PET (or MRI) (modified treated population). 
Safety Analysis Set 
All enrolled patients who receive at least 1 dose of ABI-009 
(treated population). 
Per-protocol Analysis 
Set 
All enrolled patients who do not have any prospectively defined 
protocol violations.  


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
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Progression-free rate 
at 6 months 
Progression-free rate at 6 months is the proportion of patients 
who are progression-free and alive at 6 months. 
Progression-free 
survival 
The time from the first dose date to the first observation of a 
disease progression, assessed radiologically, 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.  
 
 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
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1. 
INTRODUCTION 
1.1. 
Colorectal Cancer 
Colorectal cancer is the 3rd most common cancer and one of the leading causes of death 
among cancer types (Siegel, 2017). In the early stage, colorectal cancer often does not 
present symptoms and usually becomes symptomatic when it progresses to more 
advanced stages. Surgery is the most common treatment for cancers that have not 
spread, and chemotherapy and/or targeted therapy is given for patients whose cancer 
metastasized. However, the 5-year survival rate is still a dismal 14% for patients with 
metastatic colorectal cancer (mCRC) (Siegel, 2017), and improved therapeutic options 
are needed. 
1.2. 
Treatment Options in Colorectal Cancer 
1.2.1. 
FOLFOX and Bevacizumab in Colorectal Cancer 
Oxaliplatin with infusional 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFOX) and 
irinotecan with infusional 5-FU and LV (FOLFIRI) are standard chemotherapy regimens 
for the first-line treatment of patients with mCRC (NCCN, 2017). Since its approval for the 
first-line treatment of mCRC in 2004, bevacizumab, a VEGF-A inhibitor, has become a 
standard treatment option in combination with chemotherapy for patients with mCRC. In 
particular, mFOLFOX6 combined with bevacizumab are now well established for 
treatment of metastatic colorectal carcinomas (Hochster, 2008; Saltz, 2008; Bendell, 
2012; Strickler, 2012; Baba, 2017; Rivera, 2017). The median progression-free survival 
(PFS) were 9-11 months, with approximately 50% overall response rates (ORR) in most 
studies (Hochster, 2008; Saltz, 2008; Bendell, 2012; Strickler, 2012; Baba, 2017; Rivera, 
2017), and improvement in reducing tumor burden and time to progression in the first-line 
setting is still needed. Improving efficacy of first-line treatments may help in optimizing 
the overall treatment plan and improve the outcome of subsequent therapies and overall 
survival (OS) for patients in colorectal cancer. 
1.2.2. 
mTOR Inhibition in Colorectal Cancer 
The mammalian target of rapamycin (mTOR) oncogenic pathways (PI3K/AKT/mTOR) are 
frequently dysregulated in human cancers, including colorectal cancer (Wu, 2015; Laes, 
2017). mTOR is downstream of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and 
the tumor suppressor gene PTEN coding for the Phosphatase and Tensin Homolog, and 
a key regulator of cell survival, proliferation, and metabolism. Activating mutations in 
PIK3CA or null mutations in the tumor suppressor gene PTEN and subsequent loss of 
expression can lead to mTOR-pathway activation (Laes, 2017). 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 
(VEGF) (Corradetti, 2006). Consistent with its role in cell proliferation, the mTOR pathway 
is frequently overactivated in a number of human malignancies and is considered to be 
an attractive target for anti-cancer therapy. 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
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mTOR and PI3K inhibitors have been approved for the various cancer treatment, 
including renal cell carcinoma and breast cancer, and are under investigation for several 
cancer types, including mCRC. A recent phase 1/2 study that showed evidence for 
antitumor activity of everolimus, an mTOR inhibitor, in combination with mFOLFOX6 plus 
bevacizumab (standard of care) for the first-line treatment for mCRC (NCT01047293) 
(Gilcrease GW, 2012). The 6-month PF rate was 96%, at the maximum-tolerated dose 
(MTD) (Gilcrease GW, 2018), compared to a historical estimate of approximately 77% for 
mFOLFOX6 + bevacizumab (Saltz, 2008; Bendell, 2012; Baba, 2017; Rivera, 2017). The 
ORR was 53% in the intent-to-treat population and 86% for patients with PTEN loss, a 
population that typically has poorer prognosis. Evidence of anti-tumor activity correlated 
with mutation status (k-RAS, BRAF, PIK3CA) and PTEN deletion status. Thus, evaluation 
of PIK3CA or PTEN mutations or expression in combination with the mTOR activity status 
could provide additional information on disease prognosis and potential sensitivity to 
cancer treatments in future studies. While the efficacy of the mTOR inhibitor combined 
with FOLFOX/bev was highly promising, 62% patients developed grade 2 stomatitis, 
mainly related to the addition of everolimus. 
A novel mTOR inhibitor, ABI-009 (albumin-bound sirolimus nanoparticles, nab-sirolimus), 
is a solvent-free, intravenous (IV) form of sirolimus and has relatively high bioavailability. 
Dose-limiting toxicities (DLT) including mucositis/stomatitis that were observed with other 
mTOR inhibitors were not dose-limiting with ABI-009 (Gonzalez-Angulo, 2013). The 
particularly safe toxicity profile of ABI-009 allows this mTOR inhibitor to be combined with 
other therapeutics, and offers a promising new therapeutic for colorectal cancer. 
1.3. 
ABI-009 Background 
1.3.1. 
Sirolimus and Rapalogs 
Sirolimus (formerly rapamycin) is a protein kinase inhibitor that is approved for 
immunosuppression 
in 
renal 
transplant 
patients 
and 
for 
the 
treatment 
of 
lymphangioleiomyomatosis, and is under investigation for various cancer treatment. 
Sirolimus 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 (Dowling, 2010). 
Although sirolimus is an efficacious mTOR inhibitor, it has poor solubility, low oral 
bioavailability, and produces DLTs, including mucositis and stomatitis (O'Donnell, 2008; 
Yuan, 2009). Marketed sirolimus analogs are temsirolimus and everolimus. 
Temsirolimus, a prodrug of sirolimus requiring conversion to sirolimus in vivo, is approved 
for the treatment of kidney cancer. Everolimus is approved for pediatric and adult patients 
with subependymal giant cell astrocytoma, 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(Hanna, 2008; Molina, 2011; Yao, 2011; Baselga, 
2012; Thompson, 2012). 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
Confidential and Proprietary 
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Amendment 2.1 
 
 
Oral sirolimus 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 (de Oliveira, 2011; Albiges, 2012; Qi, 2013). The most frequently 
occurring grade 3 or 4 adverse events (AEs) were hyperglycemia (17%), 
hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%) (Zhou, 2010). 
1.3.2. 
ABI-009 (nab-Sirolimus) 
The novel nanoparticle albumin-bound sirolimus (nab-sirolimus, ABI-009) is freely 
dispersible in saline and is suitable for IV administration, and has produced both a 
favorable safety profile and evidence of efficacy in patients with metastatic solid tumors 
(Gonzalez-Angulo, 2013). 
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 
(Gradishar, 2005). This suggests that the nab form of sirolimus may also produce similar 
advantages over the standard sirolimus. 
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 (Kremer, 2002; Kratz, 2008). Albumin circulating in the 
bloodstream can interact with gp60 to initiate caveolae-mediated transcytosis to reach 
tumor cells (Schnitzer, 1992; Schnitzer, 1995). Indeed, nab-paclitaxel transcytosis across 
the epithelial monolayer was dependent on caveolae formation (Desai, 2006). 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 (Desai, 2006). 
1.3.3. 
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 1A 
and B, below), including colorectal and pancreatic cancer (De, 2007; Desai, 2009; Trieu, 
2009; Cirstea, 2010; Kennecke, 2011). This dose level correlates to approximately 120 
mg/m2 in human. These findings are consistent with published information on sirolimus 
as an mTOR inhibitor and the role of mTOR in tumor growth (Fasolo, 2012). 
 
 




ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
Confidential and Proprietary 
25 
Amendment 2.1 
 
 
Figure 2: ABI-009 Administered IV Compared with Equal Weekly Dosing of Oral 
Sirolimus and Oral Everolimus  
 
Preclinical pharmacokinetic (PK) studies in rats showed that IV ABI-009 exhibited linear 
PK with respect to dose and large volume of distribution (Vz), due to efficient tissue 
extraction of sirolimus from the central blood compartment (De, 2007). Shortly after 
dosing, tissue sirolimus level was 3-5 folds 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 sirolimus literature (Sehgal, 2003), 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 
Good Laboratory Practice (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 delivered every 4 days for 3 cycles. Nonclinical toxicology studies of 
ABI-009 showed no new or unexpected toxicity compared to what is already known for 
sirolimus and other rapalogs (Pfizer, 2011a; Pfizer, 2011b; Novartis, 2017). 
1.3.4. 
Clinical Studies with ABI-009 
In a phase 1 dose-finding, tolerability, and PK study conducted at MD Anderson Cancer 
Center (Protocol CA401, NCT00635284), ABI-009 was well tolerated with evidence of 
responses and SD in various solid tumors including renal cell carcinoma, bladder cancer, 
and colorectal cancer, all of which typically overexpress mTOR (Gonzalez-Angulo, 2013). 
Twenty-six patients were treated with 45, 56.25, 100, 125, or 150 mg/m2 ABI-009 per 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
Confidential and Proprietary 
26 
Amendment 2.1 
 
 
week for 3 weeks, followed by a week of rest (28-day cycle, qw3/4). ABI-009 was 
administered IV. The MTD was established at 100 mg/m2. 
Nineteen patients were evaluable for efficacy. One patient in the 45 mg/m2 (95 mg actual 
sirolimus dose) cohort, diagnosed with adenocarcinoma of the kidney and with bone and 
intrathoracic metastases, had a confirmed PR. The target lesion of this patient was 
reduced by 35.1% and the duration of response lasted 183 days. Two (11%) patients (at 
doses 45 and 125 mg/m2, with actual sirolimus doses of 88 mg and 193 mg, respectively) 
had an overall tumor evaluation of stable disease (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 MTD 
of 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 (SAE), including arrhythmia (grade 
2) and mood alteration (grade 3) both in the 125 mg/m2 cohort, vomiting (grade 3) in the 
45 mg/m2 cohort, and dyspnea (grade 3) in the 100 mg/m2 cohort. 
The most common hematologic AEs, for all cohorts and grades, were thrombocytopenia 
(58%), followed by hypokalemia (23%), and 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.  
Currently, there are several ongoing trials investigating the safety and efficacy of single-
agent ABI-009 in various disease areas, including a trial in patients with malignant 
perivascular epithelioid tumors (PEComas), a rare type of soft-tissue tumors 
(NCT02494570). The particularly safe toxicity profile of ABI-009 allows this mTOR 
inhibitor to be combinable with other therapeutics and a trial in patients with advanced 
STS is currently evaluating the combination of ABI-009 and nivolumab (NCT03190174). 
1.4. 
Rationale for Combination of ABI-009 with FOLFOX and Bevacizumab in 
Colorectal Cancer 
In the phase 1/2 study (NCT01047293) of everolimus added to mFOLFOX6 + 
bevacizumab described in Section 1.2.2, the observed 96% PF rate at 6 months 
(compared with a historical estimate of approximately 77% for mFOLFOX6 + 
bevacizumab) (Saltz, 2008; Bendell, 2012; Baba, 2017; Rivera, 2017) and the observed 
86% ORR in patients with PTEN loss (compared with 53% in the all patients) suggest that 
mTOR inhibition may be beneficial when added to the standard of care treatment. On the 
basis of the safety profile of single agent ABI-009, the evidence of antitumor activity in 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
Confidential and Proprietary 
27 
Amendment 2.1 
 
 
various solid tumors (Section 1.3.4, NCT00635284), as well as the tumor xenograft study 
demonstrating improved therapeutic potential of ABI-009 vs oral sirolimus or everolimus, 
we propose a phase 1/2 assessment of the combination of ABI-009 with mFOLFOX6 and 
bevacizumab as first-line treatment for patients with mCRC. The goal of this study is to 
demonstrate that ABI-009 combined with the standard of care a) is safe and efficacious 
and b) suggests an improved benefit in patients with PTEN loss.  
1.5. 
Rationale for Starting Dose selection and Schedule of ABI-009, 
mFOLFOX6, and Bevacizumab 
Considering the safety profile of FOLFOX and bevacizumab, a dose lower than the MTD 
of single-agent ABI-009 is recommended when combined FOLFOX/bevacizumab. The 
original planned starting dose of 30 mg/m2 ABI-009 given IV weekly for 3 weeks with a 
week of rest (qw3/4) gives a wide >3x safety margin for patients with advanced colorectal 
cancer over the established MTD of 100 mg/m2. This dose, assuming a body surface area 
(BSA) of 1.7, is 51 mg/week (or 38 mg/week on average in a 4-week cycle), which is 
within the therapeutic range for rapalogs:   
• In the phase 1/2 study with everolimus combined with mFOLFOX6 and 
bevacizumab NCT01047293) (Gilcrease GW, 2012), the MTD of everolimus was 
7.5 mg/day (52.5 mg/week), which is similar to the dose range evaluated in this 
study. 
• Using the PK data from the phase 1 study (Gonzalez-Angulo, 2013), linear 
modeling of sirolimus blood concentration predicts that 1 week after 10 and 20 
mg/m2 ABI-009 IV administration, therapeutic trough sirolimus levels are still 
maintained (7.11 and 14.22 ng/mL, respectively, Aadi data on file). Thus, potential 
dose reduction from the starting dose of 30 mg/m2 should still result in therapeutic 
levels. 
• ABI-009 has shown similar safety profile to other rapalogs, even at a higher dose 
of 100 mg/m2. In particular, mucositis/stomatitis that were observed with other 
mTOR inhibitors has not been dose-limiting with ABI-009. 
The qw3/4 schedule allows for coordinating the every-2-week administration of 
mFOLFOX6 and bevacizumab and was the studied schedule in the first-in-human study 
for ABI-009 (CA401, NCT00635284). 
mFOLFOX6 and bevacizumab will be given as in the phase 1/2 study (NCT01047293). 
mFOLFOX6:  oxaliplatin 85 mg/m2 IV with leucovorin 400mg/m2 IV over 2 hours plus FU 
400 mg/m2 IV bolus and 2,400 mg/m2 continuous infusion over 46 hours every 2 weeks. 
Bevacizumab will be given at 5 mg/kg every 2 weeks. 
While the original qw3/4 schedule starting at 30 mg/m2 was based on the studied 
schedule, with Amendment 2, the every-2-week ABI-009 dosing schedule with a lower 
starting dose of 20 mg/m2 has been implemented based on a) alignment with the every-
2-week standard of care (FOLFOX + bevacizumab) dosing schedule and b) to allow 
sufficient time to recover from the potential cumulative myelosuppressive effect of the 
FOLFOX+bevacizumab+ABI-009 regimen given on Day 1. 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
Confidential and Proprietary 
28 
Amendment 2.1 
 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives  
Objectives in Phase 1 
Primary 
• To identify the recommended phase 2 dose (RP2D) of ABI-009 in combination with 
mFOLFOX6 and bevacizumab 
Secondary 
• To evaluate preliminary efficacy and safety of ABI-009 in combination with 
mFOLFOX6 and bevacizumab at the RP2D 
Objectives in Phase 2 
Primary 
• To evaluate the efficacy of ABI-009 in combination with mFOLFOX6 and 
bevacizumab at the RP2D for all patients as well as based on PTEN status 
Secondary 
• To evaluate the safety and toxicity profile of ABI-009 in combination with 
mFOLFOX6 and bevacizumab at the RP2D 
Exploratory 
• To identify predictive molecular biomarkers for patients treated with ABI-009 in 
combination with mFOLFOX6 and bevacizumab  
2.2. 
Endpoints 
Endpoints in Phase 1 
Primary Endpoint 
• Identify DLTs and the MTD (defined as ≤1 of 6 patients with a DLT) of ABI-009 in 
combination with mFOLFOX6 and bevacizumab 
Secondary Endpoints 
• Safety profile of dose cohorts analyzed separately and together 
• Disease control rate (DCR) assessed by investigators based on RECIST v1.1, 
dose cohorts analyzed separately and together 
Endpoints in Phase 2 – Data from both phase 1 and 2 
Primary Endpoint 
• PF rate at 6 months in patients treated with ABI-009 in combination with 
mFOLFOX6 and bevacizumab at the RP2D based on investigator assessment 
(RECIST v1.1) 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
Confidential and Proprietary 
29 
Amendment 2.1 
 
 
Secondary Endpoint 
• 
Median PFS, ORR, duration of response (DOR), and DCR at the RP2D and all 
dose cohorts, based on investigator assessed RECIST v1.1 for all patients and 
based on PTEN status 
• 
PF rate at 6 months based on PTEN status 
• 
Safety at RP2D, including patients from phase 1, based on National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
Exploratory endpoints 
• Biomarkers: 
o Pre-treatment metastatic tumor biopsy: (fresh or archival) are required from 
all patients to assess baseline biomarker and mutational analysis, including 
PTEN loss evaluation, PIK3CA and Ras mutational status, and mTOR 
pathway markers (including, but not limited to S6K, 4EBP1). In particular, 
PIK3CA mutations and PTEN loss will be analyzed by IHC to evaluate as 
potential predictive biomarkers of response to mTOR inhibition. If tissue from 
metastatic site is not available, primary lesion tissue is acceptable. Reports 
on mutational status will be collected from all patients, if available. 
o Blood samples: for cell-free plasma DNA collection (pretreatment, C3 and C6 
D1 post-treatment, upon disease progression, and/or end of last dose of 
treatment) for all patients. Molecular analysis of circulating DNA assay using 
next generation sequencing to assess changes over time as response to 
therapy of the prevalence of mutations identified in the baseline tumor samples 
 Nucleic acids extracted from blood can also be used to investigate whether 
circulating tumor nucleic acids are associated with disease progression 
2.3. 
Study Design 
This study is a prospective phase 1/2, single arm, open-label, multi-institutional study to 
identify the RP2D and determine the efficacy and safety profile of ABI-009 administered 
as first-line therapy in combination with mFOLFOX6 and bevacizumab in patients with 
advanced or mCRC. A cycle will consist of 4 weeks, ie 28 days. 
The study will be conducted in compliance with International Conference on 
Harmonisation (ICH) Good Clinical Practices (GCPs). 
The starting dose and schedule of ABI-009 is 20 mg/m2 every 2 weeks on Days 1 and 15 
(28-day cycle) by IV infusion over 30 minutes (+10 mins window allowed, ie 30-40 mins 
infusion). Bevacizumab and mFOLFOX6 will be administered every 2 weeks, starting 
Cycle 1, Day 1. Patients receiving ABI-009 qw3/4, the original dosing schedule prior to 
Amendment 2, will drop Day 8 ABI-009 and switch to the every-2-week schedule. 
Modified FOLFOX6 regimen: Oxaliplatin 85 mg/m2 IV with LV 400 mg/m2 IV over 2 hours 
plus FU 400 mg/m2 IV bolus and 2,400 mg/m2 continuous infusion over 46 hours every 2 
weeks. Dose modifications of each agent in FOLFOX may be made independently based 
on the specific types of toxicities observed. Bevacizumab may be skipped or discontinued 
for bevacizumab-related toxicities, but the dose is not reduced. 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
Confidential and Proprietary 
30 
Amendment 2.1 
 
 
Patients will continue to therapy until disease progression, unacceptable toxicity, until in 
the opinion of the investigator the patient is no longer benefiting from therapy, or at the 
patient’s discretion. After 6 months of therapy, single agent ABI-009 may be continued at 
the discretion of the investigator if mFOLFOX6 and/or bevacizumab are discontinued due 
to toxicity or achievement of maximum benefit per treating physician. 
Figure 3A. Original Study Schema for ABI-009 given qw3/4 (original dosing 
schedule) 
 
 
With Amendment 2, an alternate dosing schedule is implemented replacing the original 
schedule above to allow evaluation of ABI-009 given every 2 weeks, aligned with the 
dosing schedule of the standard of care, FOLFOX + bevacizumab. Study Schema for 
every-2-week dosing schedule implemented with Amendment 2. Patients receiving ABI-
009 qw3/4 on the original schedule may permanently drop Day 8 dosing if ≥2 Day-8 ABI-
009 had to be skipped due to toxicity. 
 
Figure 3B. Study Schema for ABI-009 given every 2 weeks, implemented with 
Amendment 2 
 
 
 
Dose-finding Phase 1 Portion of the Study:   
Dose levels of ABI-009 will be tested in cohorts of 3 patients each using the 3+3 dose-
finding design. The original starting dose was 30 mg/m2 ABI-009 given weekly for 3 weeks 
followed by a week of rest (qw3/4, 28-day cycle), and dose levels could be escalated to 
45 and 60 or de-escalated to 20 and 10 mg/m2. With Amendment 2, the new starting dose 
was 20 mg/m2 given once every 2 weeks on Days 1 and 15(28-day cycle). 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
Confidential and Proprietary 
31 
Amendment 2.1 
 
 
Table 1. Dose Levels of ABI-009 Implemented with Amendment 2 
Dose Levels 
ABI-009 in mg/m2 
IV every 2 weeks 
-2 
10 
-1 
15 
1 
20 
2 
30 
3 
45 
Escalation to the next dose level with a new cohort of 3 patients will occur after no DLT 
was observed in the first 2 cycles. There will be no intra-patient dose escalation allowed. 
If a DLT occurs in a cohort, additional 3 patients will be recruited to the cohort. If no further 
DLTs occur, then a new cohort of 3 patients at the next higher dose level can be enrolled. 
If 2/6 patients at dose level 1 experience a DLT, then that cohort will be closed to further 
enrollment and 3 patients will be enrolled at the next lower dose level, and so on.  
The MTD is the highest dose level in which ≤1 patient has a DLT.  The RP2D is identified 
based on the totality of safety and efficacy data. 
Once the dose-finding portion of the study is concluded and RP2D is identified, patients 
receiving a lower dose may be allowed to receive ABI-009 at the RP2D, based on the 
investigator judgment and discussion with the medical monitor. 
Phase 2 Portion of the Study:  
Phase 2 will be an open label single arm study in approximately 40 patients at the RP2D 
determined from phase 1. Assuming a 10% attrition rate, at least 44 patients would need 
to be enrolled for the phase 2 portion of the study. Patients enrolled in the phase 1 portion 
at the RP2D will be included in phase 2 for response and safety evaluation.  
Figure 4. Study Design Implemented with Amendment 2 
 
 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
Confidential and Proprietary 
32 
Amendment 2.1 
 
 
2.4. 
Study Duration, End of Study, End of Treatment, End of Treatment Visit, 
Follow-up Period 
The study is expected to take approximately 24 months from first patient enrolled to last 
patient follow-up, including approximately 12 months of enrollment period, an estimated 
12 months of treatment (or until treatment is no longer tolerated).   
End of Treatment (EOT) for a patient is defined as the date of the last dose of ABI-009 or 
FOLFOX/bevacizumab, whichever is later. End of Treatment Visit for a patient is when 
safety assessments and procedures are performed after the last treatment (should be 
within 1 month of 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.  
Follow-up period is the 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 of new 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/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
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Amendment 2.1 
 
 
3. 
STUDY POPULATION 
3.1. 
Number of Patients 
Phase 1: The sample size for phase 1 is anticipated to be 5 to 18 patients. 
Phase 2: The sample size for phase 2 will be a total of approximately 40 patients, 
including the patients from phase 1 who initiated treatment at the RP2D.  
Patients who fail to become evaluable for the primary endpoint because of a missing 
follow-up CT/PET (or MRI) will be replaced. Assuming a 10% attrition rate, at least 44 
patients would need to be enrolled for the phase 2 portion of the study (inclusive of the 
phase 1 patients at RP2D). 
3.2. 
Inclusion Criteria  
A patient will be eligible for inclusion in this study only if all of the following criteria are 
met during screening: 
1. Patients with histologically confirmed advanced or metastatic colorectal 
cancers for whom chemotherapy is indicated. If biopsy from metastatic site is 
not feasible, imaging may be used to confirm the presence of metastasis in a 
patient that is already previously histologically confirmed for colorectal cancer. 
2. Patients must not have had prior chemotherapy for advanced or metastatic 
disease. Patients could have received adjuvant chemotherapy or adjuvant 
chemo-radiotherapy. 
3. Patients must have at least 1 measurable site of disease according to RECIST 
v1.1 that has not been previously irradiated. If the patient has had previous 
radiation to the marker lesion(s), there must be radiological evidence of 
progression since the radiation. 
4. Eligible patients, 18 years or older, with Eastern Cooperative Oncology Group 
(ECOG) performance status 0, 1, or 2. 
5. Patients must not have been previously treated with an mTOR inhibitor. 
6. Adequate liver function: 
a. Total bilirubin ≤1.5 x upper limit of normal (ULN) mg/dL (except in the dose 
escalation phase, in which the total bilirubin is <ULN) 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 x ULN (<5 x ULN if the patient has liver metastases). 
7. Adequate renal function: 
a. Serum creatinine ≤2 x ULN or creatinine clearance >50 cc/hr (Cockcroft-
Gault). 
8. Adequate biological parameters: 
a. Absolute neutrophil count (ANC) ≥1.5 × 109/L 
b. Platelet count ≥100,000/mm3 (100 × 109/L) 
c. Hemoglobin ≥9 g/dL. 
9. Fasting serum triglyceride ≤300 mg/dL; fasting serum cholesterol ≤350 mg/dL. 
10. INR and PTT <1.5 x ULN (anticoagulation is allowed if target INR <1.5 on a 
stable dose of warfarin or on a stable dose of LMW heparin for >2 weeks at 
time of enrollment). 


ABI-009/mFOLFOX6/Bev 
Protocol: COLO-007                                                                                        
Aadi Bioscience 
 
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Amendment 2.1 
 
 
11. Minimum of 4 weeks since any major surgery, completion of radiation, or 
completion of all prior systemic anticancer therapy, and ≥6 months since 
adjuvant FOLFOX therapy (adequately recovered from the acute toxicities of 
any prior therapy, including neuropathy should be grade ≤1). 
12. 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 throughout 3 months after 
last dose of IP 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 and throughout 3 months after last dose of IP. A 
second form of birth control is required even if he has undergone a successful 
vasectomy. 
13. Life expectancy of >3 months, as determined by the investigator. 
14. Ability to understand and sign informed consent. 
15. 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 
during screening: 
1. History of severe and uncontrolled allergic reactions to bevacizumab. 
2. Prior treatment with FOLFOX or bevacizumab within the preceding 4 weeks. 
3. Patients currently receiving or have received anticancer therapies within 4 weeks 
of the start of study treatment (including chemotherapy, radiation therapy, 
antibody-based therapy, etc.). 
4. Patients, who have had a major surgery or significant traumatic injury within 4 
weeks of start of study drug, patients who have not recovered from the side effects 
of any major surgery (defined as requiring general anesthesia) or patients that may 
require major surgery during the course of the study. 
5. Chronic treatment with systemic steroids or another immunosuppressive agent; 
topical or inhaled corticosteroids are allowed. 
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. Patients who have any severe and/or uncontrolled medical or psychiatric 
conditions or other conditions that could affect their participation including: 
a. 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 


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surgery) prior to start of treatment in this study and should not be receiving 
chronic corticosteroid therapy for the CNS metastases. 
b. Unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction ≤6 months prior to first study treatment, serious uncontrolled cardiac 
arrhythmia or any other clinically significant cardiac disease. 
c. Pre-existing severely impaired lung function as defined as spirometry and 
DLCO that is 50% of the normal predicted value and/or O2 saturation that is 
88% or less at rest on room air (Note: spirometry and PFTs not required to be 
performed unless clinically indicated). 
d. Uncontrolled diabetes as defined by fasting serum glucose >1.5x ULN or by 
HbA1c >8% despite adequate therapy. 
e. Any active (acute or chronic) or uncontrolled infection/ disorders.   
f. Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by the treatment with the study therapy. Note, controlled non-
melanoma skin cancers, carcinoma in situ of the cervix, resected incidental 
prostate cancer, or other adequately treated carcinoma-in-situ may be eligible, 
after documented discussion with the sponsor / medical monitor. 
g. Known liver disease such as cirrhosis or severe hepatic impairment (Child-
Pugh class C). 
h. Uncontrolled hypertension (systolic blood pressure ≥160 mm Hg and/or 
diastolic blood pressure ≥90 mm Hg. 
8. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary 
hypertension. 
9. Patients with history of intestinal perforations, fistula, hemorrhages and/or 
hemoptysis ≤6 months prior to first study treatment. 
10. A known history of HIV seropositivity. 
11. Active Hepatitis B or Hepatitis C. Note: A detailed assessment of Hepatitis B/C 
medical history and risk factors must be done at screening for all patients.  HBV 
DNA and HCV RNA PCR testing are required at screening for all patients with a 
positive medical history based on risk factors and/or confirmation of prior 
HBV/HCV infection. 
12. Patients with an active bleeding diathesis or on oral anti-vitamin K medication 
(except low dose warfarin [Coumadin] or heparin). 
13. Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to 
receiving the first dose of ABI-009. Additionally, use of any known CYP3A4 
substrates with narrow therapeutic window (such as fentanyl, alfentanil, 
astemizole, cisapride, dihydroergotamine, pimozide, quinidine, terfanide) within 
the 14 days prior to receiving the first dose of ABI-009. 


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4. 
TABLE OF EVENTS 
The schedule of assessments in Table 2 outlines the specific time points for study 
assessments. 
 




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a All visits are allowed to occur in a window of ±3 days unless otherwise specified.  
b Baseline screening visit will be done within 28 days prior to study treatment Day 1.  
c Days 8 and 22 evaluations are not required with every-2-week dosing implemented with Amendment 2.  
d End of Treatment-phase (EOT) Visit should be within 1 month of last study treatment with either ABI-009 or mFOLFOX6/bevacizumab, whichever 
is later. Follow up will be every 12 weeks, after EOT or last visit till study closes or withdrawal of consent, via phone call. 
e Monitor ECG in all patients in Cycle 1 Days 1and 15, when ABI-009 infusion is given. In each case ECG is to be monitored during infusion at 
around the 30 min time point after start of infusion to coincide with the end of infusion ±10 mins. 
f Ensure that metastatic tumor samples are collected from all patients for biomarker analysis, either fresh-frozen or formalin-fixed paraffin-
embedded (FFPE) tumor blocks or unstained slides (min 6). 
g For all female patients of childbearing potential, a serum pregnancy test will be done at screening. A urine pregnancy test will be repeated within 
72 hours before first treatment if the serum pregnancy test occurred >72 hours before dosing, and at EOT. Pregnancy tests conducted after 
screening will be recorded in the source documentation only.  
h Heights are measured only at screening. BSA will be capped at 2.0 m2 for all therapeutics that require BSA calculation (ABI-009 and FOLFOX). 
Dose recalculation due to >10% weight change is from the last known value when the weight was used for dose calculation (applies to all 
therapeutics, including bevacizumab). 
i Monitor proteinuria by dipstick urine analysis with serial urinalyses during bevacizumab therapy. For patients with a 2+ or greater urine dipstick 
reading bevacizumab treatment should be held. Patients should undergo further assessment with a 24-hour urine collection, if nephrotic syndrome 
is suspected. Suspend bevacizumab for >2 grams of proteinuria/24 hours and resume when proteinuria is < 2gm/24 hours. Discontinue 
bevacizumab in patients with nephrotic syndrome.  
j Sirolimus levels are analyzed only for patients enrolled in the dose-finding phase (phase 1). C1D1 and C1D15 post-dose samples are done 
centrally; however, all trough levels (pre-dose) are done locally. C1D1: predose (anytime) and post-dose at 0.5 hr (end of infusion), 1, 2, and 4 hrs 
after start of infusion (±10 mins); C1D15: predose (anytime) and post-dose at 0.5 hr (end of infusion, ±10 mins). Additionally, pre-dose levels will be 
analyzed on these following infusion days C2D1, C2D15, C3D1, C3D14, C4D1, and C4D15. Note, pre-dose sample collection does not have a 
specific time and window; the collection should be made on the day of dosing, prior to dosing. 
k Baseline imaging must be done within 2 weeks of C1D1, but preferably as close to the day of enrollment as possible, then every 8 weeks (±1 
week) from first treatment during the 1st year, and every 12 weeks thereafter through disease progressions, regardless of missed or out of window 
doses. If a patient discontinued treatment other than disease progression, scan should be done at EOT visit. Either CT or CT/PET scans are 
acceptable for the study but if a CT/PET scan can be done, this is preferable. PET results are only used for qualitative assessments. MRI is 
allowed, if CT is contra-indicated for a patient. The same mode of imaging at screening must be used consistently throughout the study.  
l ABI-009, mFOLFOX6, and bevacizumab must be administered after all study specific assessments are done in a visit, withABI-009 administered 
first followed by mFOLFOX6 + bevacizumab. It is recommended to limit the infusion to central line, which is used for the standard of care 
combination agents (FOLFOX + bevacizumab). 


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5. 
PROCEDURES 
5.1. 
Screening Evaluations 
This study will be conducted at least 2 US centers. Each patient who enters into the 
screening period for the study receives a unique patient identification number before any 
study-related procedures are performed. 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 sites’ 
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 ≤28 days prior to enrollment. Any questions 
regarding patient eligibility should be directed to Aadi Bioscience, Inc, 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)  
• Medical history, prior/concomitant medications and procedures evaluation: all 
medications taken ≤28 days prior to screening  
• ECG  
• Physical examination as per standard of care (including physical exam, 
medical/cancer history, ECOG performance status assessment)  
• Vital signs (eg, blood pressure, pulse, respiration rate, temperature, height, 
weight) 
• Local Laboratory Assessments: chemistry, complete blood count (CBC), 
differential, platelet count, urinalysis, pregnancy test (women of child-bearing 
potential, includes tubal ligations), HIV, hepatitis B surface antigen, hepatitis C 
antibody, fasting lipids, carcinoembryonic antigen (CEA), blood for biomarkers 
• Pre-treatment tissue collection for biomarkers 


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• CT/PET scans (or MRI, if CT is contraindicated), must be done within 2 weeks 
of C1D1, but preferably should be done as close to the day of enrollment as 
possible 
• Adverse event assessment 
A patient is considered enrolled when the investigator decides that the patient has met all 
eligibility criteria. The investigator is to document this decision and date, in the patient’s 
medical record and in/on the electronic case report form (eCRF). 
5.2. 
Treatment Period 
A patient is considered enrolled on study day 1 when the IP, ABI-009, is first administered. 
ABI-009, mFOLFOX6, and bevacizumab 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. 
5.2.1. 
Day 1 Assessment 
The following assessments will be performed on Day 1 of each cycle, unless otherwise 
specified: 
• Physical examination  
• Vital signs  
• Concomitant medication and procedures evaluation  
• ECG, Cycle 1 only 
• CBC, differential  
• Clinical chemistry panel 
• Urinalysis (to monitor proteinuria during bevacizumab therapy) 
• Fasting lipids (every even cycles) 
• Blood samples for biomarkers on C3 and C6 
• Sirolimus level, Cycles 1 through 4  
• CEA 
• ECOG performance status 
• Adverse events 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, 
coagulation, urinalysis, pregnancy test (women of child-bearing potential, includes tubal 
ligation) (see Table 3 for analyte listing). 
 


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5.2.2. 
Day 15 Assessment 
The following assessments will be performed on Day 15 of each cycle, unless otherwise 
specified: 
• Physical evaluation 
• Vital signs 
• Concomitant medication and procedures evaluation 
• ECG, Cycle 1 only  
• CBC, differential  
• Clinical chemistry panel  
• Urinalysis (to monitor proteinuria during bevacizumab therapy) 
• Sirolimus level, Cycle 1 through 4  
• Adverse event assessment 
Table 3. Analyte Listing 
Chemistry 
Hematology 
Coagulation 
Urinalysis 
Other Labs 
Sodium 
WBC 
PT 
Specific gravity Pregnancy test 
Potassium 
RBC 
PTT 
pH 
HIV 
Bicarbonate 
Hemoglobin 
INR 
Blood 
HBV sAg 
Chloride 
Hematocrit 
 
Protein 
HBV cAb 
Total protein 
MCV 
 
Glucose 
HCV Ab 
Albumin 
MCH 
 
Ketones 
Total Cholesterol  
Calcium 
MCHC 
 
Microscopic 
HDL 
Magnesium 
RDW 
 
 
LDL 
Phosphorus 
Platelets 
 
 
Triglyceride 
Sirolimus 
Glucose 
Differential: 
 
 
 
BUN 
-Neutrophils 
 
 
 
Creatinine 
-Lymphocytes 
 
 
 
Total bilirubin 
-Monocytes 
 
 
 
Alkaline phosphatase -Eosinophils 
 
 
 
AST (SGOT) 
-Basophils 
 
 
 
ALT (SGPT) 
 
 
 
 
Amylase 
 
 
 
 
Lipase 
 
 
 
 
 


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5.2.3. 
Response Assessment  
Tumor response will be assessed by CT / PET (or MRI, if CT is contra-indicated) scan of 
the chest, abdomen, and pelvis (CAP) per institutional guidelines; image preparation and 
evaluation will follow the specifications provided in the RECIST version 1.1. The same 
modality (CT or MRI) must be used at screening and throughout the study.  
CT/ PET or MRI scans to be performed at the following frequency: 
• ≤2 weeks prior to C1D1 (screening) 
• followed by every 8 weeks for the first year; then every 12 weeks until disease 
progression or unacceptable toxicity. End of Treatment Visit CT/ PET (or 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.  
5.3. 
End of Treatment Visit Assessment 
The EOT Visit is a safety follow-up visit that is to be performed within 1 month after the 
last dose of ABI-009 or mFOLFOX6 / bevacizumab, whichever is later. 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  
• Vital signs  
• Concomitant medications and procedures evaluations 
• Pregnancy test (urine test is sufficient) 
• CBC /differential 
• Chemistry panel 
• ECOG performance status 
• Imaging Assessment: CT/PET (or MRI) is to be performed at the EOT visit only 
for those patients that discontinue treatment for a reason other than disease 
progression per RECIST v1.1  
5.4. 
Sirolimus Pharmacokinetic Analysis 
Sirolimus assays will be done for patients enrolled in the dose-finding portion of the 
study. Pre-dose (trough levels) are done locally; post-dose levels are done centrally:  


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• Cycle 1 D1: pre-dose (anytime) and post-dose at 0.5 hr (±10 mins,end of 
infusion), and 1, 2, and 4hrs (±10 mins) after the start of the infusion;  
• Cycle 1 D15: predose (anytime) and 0.5 hr ((±10 mins) after start of infusion  
• Predose (anytime, prior to infusion) only on: Cycle 2 Days 1 and 15, Cycle 3 
Days 1 and 15, and Cycle 4 Days 1 and 15. 
5.5. 
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 / mFOLFOX6 
/ BEVACIZUMAB) 
6.1. 
ABI-009 plus mFOLFOX6 / Bevacizumab Dosage, Administration, and 
Schedule 
Treatment with ABI-009 combined with mFOLFOX6 / bevacizumab will continue until 
disease progression or unacceptable toxicity. A physician must be available at the time 
of administration of IP on dosing days that correspond to study visits. Supportive care per 
the institution’s normal standard of care including concomitant medications can be 
provided at the investigator’s discretion. 
As described in Section 2.3, with Amendment 2, an alternate dosing schedule is 
implemented to allow evaluation of ABI-009 given every 2 weeks, aligned with the dosing 
schedule of the standard of care, FOLFOX+ bevacizumab. The starting dose of the every-
2-week schedule is 20 mg/m2, see table below. Dose escalation to the next dose level will 
follow the same 3+3 dose-finding design as described in Section 2.3.Dose-escalation and 
de-escalation will follow the standard 3+3 rules, per Table 4. 
Table 4. Dose Levels for ABI-009 
Dose Levels 
ABI-009 in mg/m2 
IV every 2 weeks 
-2 
10 
-1 
15 
1 
20 
2 
30 
3 
45 
mFOLFOX6 (oxaliplatin 85 mg/m2 IV with leucovorin 400mg/m2 IV over 2 hours plus FU 
400 mg/m2 IV bolus and 2,400 mg/m2 continuous infusion over 46 hours every 2 weeks) 
will be combined with bevacizumab given at 5 mg/kg every 2 weeks. If oxaliplatin is 
skipped, the 2-hr infusion time may be reduced as per institutional standards. 
Levoleucovorin (Fusilev) may be administered as a substitute for leucovorin. The 
levoleucovorin dose will be 200 mg/m2 IV infusion over 2 hours, or as per institutional 
standards. The starting dose of FOLFOX + bevacizumab may also be modified as per the 
product labels and institutional standards. 
Screening or day 1 weight will be used to calculate BSA for ABI-009 and FOLFOX 
(leucovorin included) dosing; BSA will be capped at 2.0 m2 for all therapeutics that require 
BSA calculation (ABI-009 and FOLFOX). Bevacizumab dose will be calculated based on 
the actual patient weight in kilograms.  
Dose modification for weight change:  
• 
In the event of a ≥10% weight loss or gain, BSA will be recalculated. Dose 
recalculation is from the last known value when the weight was used for dose 
calculation (applies to all therapeutics, including bevacizumab). 


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6.2. 
ABI-009 Dose Modification and Stopping Rules 
If treatment cannot be administered on the planned visit date, ABI-009 may be 
administered ±3 days from the scheduled date. Prior to ABI-009 administration, patients 
must meet the following hematological requirements: 
• ANC ≥1.0 x 109/L 
• Platelet count ≥75 x 109/L 
• Hemoglobin ≥9 g/dL 
ABI-009 will be on hold up to 28 days until the patient has fulfilled these criteria. The 
maximum delay between a missed scheduled ABI-009 dose and the next one 
(whichever dose was missed) should not be longer than 28 days. Approval from the 
medical monitor is required to restart study treatment after ≥28 days of interruption 
In the event of clinically significant AE related to ABI-009 in any part of the study, ABI-
009 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 28 days of stopping therapy, then ABI-009 may be restarted.  
Dose reduction of ABI-009 to the next lower dose level should be considered as clinically 
indicated due to ABI-009-related toxicities for patients who are receiving ABI-009 at above 
the lowest dose level. In phase 1, once a dose has been reduced, it must not be increased 
to the previous level. In phase 2, 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, 
based on the opinion of the investigator. A maximum of 2 dose level reductions are 
allowed for a patient. 
Missed Doses 
When ABI-009 is missed on any days (D1 or D15) but FOLFOX (or at least 5FU) was 
given on D1 and/or D15, the cycle follows the schedule set by FOLFOX, a standard of 
care. 
Day 1 Dose Missed  
When 5FU or the entire FOLFOX regimen is missed (not given within the 3-day window) 
on CXD1 visit, the next treatment (if counts and chemistries permit) becomes Day 1 of a 
new cycle. 
Day 15 Dose Missed  
When 5FU or the entire FOLFOX regimen is missed (not given within the 3-day window) 
on CXD15 visit, the next treatment, if occurs >28 days from the previous treatment will 
become Day 1 of a new cycle. 
Dose-limiting Toxicity 
Dose-limiting toxicities will be assessed in the first 28 days of dosing (1 cycle). Patients 
need to receive 2 rounds/sessions of all chemotherapy agents in the first 28 days in order 
to be evaluable for DLT assessment, unless a delay was due to toxicity in cycle 1.  
Patients who did not receive 2 rounds of all chemotherapy agents within 28 days due to 


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toxicity will be evaluable for DLT assessment. The first 2 doses of chemotherapy can be 
given over a longer period of time but a minimum assessment of 2 weeks will be required 
for toxicity assessment after the second dose of chemotherapy. 
Definition of DLT for the Phase 1 part of the trial: 
• 
Any grade ≥3 nonhematologic toxicity (NCI CTCAE v5.0), including febrile 
neutropenia, thought to be related to the regimen, with the exception that grade 3 
nausea, vomiting, or diarrhea shall not be considered a DLT if they last less than 
5 days 
• 
Grade 3 thrombocytopenia with associated bleeding 
• 
Grade 4 anemia or thrombocytopenia related to the regimen 
• 
Grade 4 neutropenia 
ABI-009 dose modification guidelines are outlined in Table 5 for clinically significant 
toxicities that are deemed related to ABI-009.  


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Table 5. Dose Modification Algorithms for Adverse Events Possibly Related to ABI-009 and mFOFLOX6 
System/Organ 
Adverse Event 
CTCAE 
Grade v5.0 
ABI-009 
FOLFOX 
Mucosa a 
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. 
Hold chemotherapy with FOLFOX until 
≤ Grade 1. FOLFOX dose reduction is 
permitted if the treating investigator 
and the medical monitor considers this 
toxicity due to the combination. 
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. 
Hold chemotherapy with FOLFOX until 
≤ Grade 1. FOLFOX dose reduction is 
permitted if the treating investigator 
and the medical monitor considers this 
toxicity due to the combination. 
Skin and 
Subcutaneous 
Tissue 
Disorders 
Skin rash 
Grade 2 
Tolerable: Continue ABI 009 at full dose, 
monitor as clinically indicated. 
Treat with same dose. 
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. 
Treat with same dose. 
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. 
Hold chemotherapy with FOLFOX until 
≤ Grade 1. 
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 
Hold chemotherapy with FOLFOX until 
≤ Grade 1 if toxicity is with first 
administration of FOLFOX, for 
subsequent occurrences, FOLFOX 
dose reduction is permitted. 


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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. 
Hold chemotherapy with FOLFOX until 
≤ Grade 1 if toxicity is with first 
administration of FOLFOX, for 
subsequent occurrences, FOLFOX 
dose reduction is permitted. 
Metabolic 
disorders 
Hyperlipidemia 
(cholesterol, 
triglycerides) 
Grade 3 
If this is persistent for 2 months, reduce by 
1 dose level at start of next cycle. 
Treat with same dose. 
Grade 4 
If this is persistent for 1 month, reduce by 
1 dose level at start of next cycle. 
Treat with same dose. 
Hyperglycemia 
Grades 1 
and 2 
Start at home 2x/day glucose monitoring; 
initiate medical management. 
Treat with same dose. 
Grade 3 
Initiate medical management; If recurrent 
post ABI-009 despite adequate medical 
management, reduce by 1 dose level. 
Treat with same dose. 
Grade 4 
Initiate medical management, hold ABI-
009 until grade 2 or less, restart 1 dose 
level lower 
Treat with same dose. 
Hematologic 
toxicity 
Thrombocytope
nia, 
Neutropenia, 
Anemia 
Grade 2 
ABI-009 can be administered if meeting 
the following hematological requirements: 
ANC ≥1000 cells/mm3, platelets ≥75,000 
cells/mm3 and hemoglobin ≥9 g/dL. 
The ANC must be ≥1000 cells/mm3 
and the platelet count ≥75,000 
cells/mm3 on the day of planned 
treatment. If these minimum 
requirements are not met on the day of 
planned treatment, treatment with 
mFOLFOX6 chemotherapy will be 
delayed until recovery occurs. 
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 ≥1000 
For grade 3 or 4 neutropenia or 
thrombocytopenia, delay 
chemotherapy until the ANC ≥1000 
cells/mm3 and the platelet count 


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cells/mm3, platelet count ≥75,000 
cells/mm3 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. 
≥75,000 cells/mm3, then resume 5-FU 
and oxaliplatin at 1 lower dose level. 
 
For febrile neutropenia (defined as 
ANC <1000 cells/mm3 and T ≥38.5°C), 
delay chemotherapy until absolute 
granulocyte count ≥1200 cells/mm3 and 
the platelet count ≥75,000 cells/mm3, 
then resume 5-FU and oxaliplatin at 1 
lower dose level. 
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. 
For noninfectious pneumonitis, if cough is 
troublesome, prescribe corticosteroids. 
 
 
 
 
 
Consider holding chemotherapy till 
resolution. 
Grade ≥3 
Permanently remove patient from protocol 
treatment. 
For grade 3 noninfectious pneumonitis, 
prescribe corticosteroids if infection is 
ruled out. Hold ABI-009 until recovery to ≤ 
grade 1; may restart within 3 weeks at 
reduced dose level if evidence of clinical 
benefit. Patients will be withdrawn from the 
study if they fail to recover to ≤ grade 1 
within 3 weeks. 
For grade 4 noninfectious pneumonitis, 
discontinue ABI-009. 
a The combination of ABI-009 with mFOLFOX-6 and bevacizumab may potentiate the risk of stomatitis and prophylactic approaches to prevent 
stomatitis such as steroid mouthwash (10 mL dexamethasone 0.1 mg/mL oral solution four times daily) could be considered for those who develop or at 
risk for stomatitis.


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6.3. 
mFOLFOX6 and Bevacizumab Dose Modification and Stopping Rules 
Dose modifications should follow the package insert for each therapeutic agent. The 
table below indicates dose modification levels for each of the agents in mFOLFOX6 for 
which dose modifications will be allowed.  Dose adjustments of each agent may be 
made independently based on the specific types of toxicities observed.  Only those 
agents specified in the sections below should be dose reduced.  If dose reduction 
beyond -3 levels for any chemotherapeutic agent is required, that agent should be 
discontinued. 
Table 6. mFOLFOX6 Dose Reductions 
Agent 
Initial Dose 
-1 
-2 
-3 
Oxaliplatin (mg/m2  
85 
65 
50 
40 
5-FU bolus (mg/m2) 
400 
320 
270 
230 
5-FU infusion (mg/m2 / 46-48 
hrs) 
2400 
1920 
1600 
1360 
Note: If any infusion of 5-FU is to be skipped, leucovorin must also be skipped. The 5-FU bolus, along with 
leucovorin may be dropped after the DLT observation period (1st cycle) in phase 1, and anytime in phase 2 
based on the discretion of the investigator. 
Bevacizumab dose is always 5 mg/kg.  Bevacizumab may be skipped or discontinued as 
described below, but the dose is not reduced. 
Patients may continue on study if bevacizumab, oxaliplatin, or 5-FU need to be 
discontinued.  If bevacizumab is discontinued, the bi-weekly urine protein testing will not 
be required. Single agent ABI-009 may be continued if mFOLFOX6 and/or bevacizumab 
are discontinued due to toxicity or achievement of maximum benefit in the opinion of the 
investigator and approval of the medical monitor and sponsor.   
Patients who have unacceptable toxicity (eg, cumulative neurotoxicity, allergy) due to 
oxaliplatin but do not have progressive disease may modify or discontinue oxaliplatin and 
continue on study with 5-FU/leucovorin, bevacizumab and ABI-009 until progressive 
disease or intolerance. Conversely, patients who have unacceptable toxicity due to 
bevacizumab or ABI-009 may discontinue bevacizumab and/or ABI-009 and continue on 
study with the other agents until progressive disease or intolerance.  
6.3.1. 
Oxaliplatin-related Neurotoxicity 
Dose-limiting neurotoxicity is common after oxaliplatin treatment, with both acute and 
chronic manifestations. Neuropathic symptoms may resolve within a week (acute); 
however, with increasing cumulative dose, severe chronic sensory neuropathy may, 
characterized by distal paresthesia and numbness, leading to functional disability. The 
following dose modifications are recommended for oxaliplatin-related neurotoxicity, 
Table 7: 


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Table 7. Oxaliplatin Dose Modification for Neurotoxicity 
Paresthesias/dysesthesias 
Duration of Acute Toxicity a 
Persistent 
Toxicity b 
1-7 Days 
>7 Days 
Between Cycles 
Grade 1: 
Paresthesias/dysesthesiasc 
of short duration that resolve 
and do not interfere with 
function 
No change 
No change 
No change 
Grade 2: 
Paresthesias/dysesthesiasc 
interfering with function, but 
not activities of daily living 
No change 
No change 
Decrease 
oxaliplatin dose by 
one dose level 
Grade 3: 
Paresthesias/dysesthesiasc 
with pain or with functional 
impairment that also 
interfere with activities of 
daily living 
No change 
Decrease 
oxaliplatin dose by 
one dose level 
Stop oxaliplatin 
(continue all other 
agents until PD) 
Grade 4: Persistent 
Paresthesias/dysesthesiasc 
that are disabling or life-
threatening 
Stop oxaliplatin 
(continue all other 
agents until PD) 
Stop oxaliplatin 
(continue all other 
agents until PD) 
Stop oxaliplatin 
(continue all other 
agents until PD) 
a Acute toxicity is defined as reversible primary peripheral sensory neuropathy that is of early onset, 
occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs 
with further dosing. 
b Persistent toxicity (> 14 days) is defined as primarily peripheral, sensory neuropathy that is usually 
characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception 
that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from 
impaired proprioception). 
c May be cold-induced. 
6.4. 
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. 
6.4.1. 
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 ≥3x ULN.  


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• 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) 
6.4.2. 
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: 
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).   


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• 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. 
6.4.3. 
Overdose  
On a per dose basis, an overdose is defined as 10% over the protocol-specified dose of 
ABI-009 or mFOLFOX6 / bevacizumab 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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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 sirolimus 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 Bioscience or sponsor 
nominated Contract Research Organization monitoring teams for verification of proper 
study drug storage. 
7.2. 
ABI-009, FOLFOX, and Bevacizumab Accountability, Disposal, and 
Compliance 
For ABI-009, only completely unused study drug vials should be retained by the site until 
a representative from Aadi Bioscience 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 Bioscience or authorized Aadi 
Bioscience-designated monitoring personnel for the purpose of accounting for the study 
drug supply. Inspections of the study drug supply for inventory purposes and assurance 
of proper storage will be conducted as necessary. Any significant discrepancy will be 
recorded and reported to Aadi Bioscience 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 FOLFOX / bevacizumab, the investigator, or designee, shall record the dispensing 
of study drug to patients. The study drug record will be made available to Aadi 
Bioscience or authorized Aadi Bioscience-designated monitoring personnel for the 
purpose of accounting for the use of the drug. 
Accurate recording of all FOLFOX / bevacizumab administration will be made in the 
appropriate section of the patient’s CRF and source documents. The investigator or 


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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 and Use 
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 the Pharmacy Manual, 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. 
7.4. 
Receipt and Return of ABI-009 
The process for handling the receipt and return of the study drug supplies are described 
in the Pharmacy Manual. 


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8. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
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 8.2. 
Concomitant therapies are to be collected from the signing of informed consent through 
the EOT Visit. Use of prohibited medications and procedures will be evaluated and 
documented during screening and on study. Therapy name including indication, dose, 
frequency, route, start date and stop date will be recorded on each patient’s CRF(s). 
8.1. 
Permitted Medications and Procedures 
The investigator must be informed as soon as possible about any medication taken from 
the time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the 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-diarrheals, 
and analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines. G-CSF 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.  
8.2. 
Prohibited Medications and Procedures 
The use of certain medications, and illicit drugs within 5 half-lives or 28 days, whichever 
is shorter prior to the first dose of study drug and for the duration of the study will not be 
allowed. If a prohibited medication is required for single use (such as for a procedure) 
while study drug is held, the Aadi Bioscience medical monitor can approve such use. 
The following medications or non-drug therapies are prohibited: 
• Other anti-cancer therapy while on treatment in this study. 
• Antiretroviral drugs (patients with known HIV are ineligible for study participation). 
• Herbal remedies (eg, St. John’s wort) unless approval is granted by the medical 
monitor. 
• Sirolimus is metabolized primarily by CYP3A4. Drugs that are strong inhibitors or 
inducers of CYP3A4 may only be used under special circumstances (eg, as a 
single use for a procedure) while treatment with study drug is interrupted. The list 
may be modified based on emerging data.  


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• Use of any known CYP3A4 substrates with narrow therapeutic window (such as 
fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, 
terfanide) within the 14 days prior to receiving the first dose of ABI-009.  Other 
medications may be allowed if there is agreement between the sponsor and 
investigator 
• Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to 
receiving the first dose of ABI-009  


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Study Endpoints 
Primary Endpoint:  
• Phase 1:  DLTs and MTD of ABI-009 in combination with mFOLFOX6 and 
bevacizumab 
• Phase 2: PF rate at 6 months in patients treated with ABI-009 at the RP2D, in 
combination with mFOLFOX6 and bevacizumab, assessed by investigators  
Secondary Endpoint(s): data both from phase 1 and 2 
• Phase 1:   
o Safety profile of dose cohorts analyzed separately and together 
o DCR assessed by investigators, dose cohorts analyzed separately and 
together  
• Phase 2:  
o Median PFS, ORR, DOR, and DCR assessed by investigator for all 
patients and based on PTEN status 
o PF rate at 6 months based on PTEN status 
o Safety at RP2D 
Exploratory Endpoint(s): 
• Biomarkers: 
o Pre-treatment metastatic tumor biopsy: (fresh or archival) are required 
from all patients to assess baseline biomarker and mutational analysis, 
including PTEN loss evaluation, PIK3CA and Ras mutational status, 
and mTOR pathway markers (including, but not limited to S6K, 
4EBP1). In particular, PIK3CA mutations and PTEN loss will be 
analyzed by IHC to evaluate as potential predictive biomarkers of 
response to mTOR inhibition. If tissue from metastatic site is not 
available, primary lesion tissue is acceptable. Reports on mutational 
status will be collected from all patients, if available. 
o Blood samples: for cell-free plasma DNA collection (pretreatment, C3 
and C6 D1 post-treatment, upon disease progression, and/or end of last 
dose of treatment) for all patients. Molecular analysis of circulating DNA 
assay using next generation sequencing to assess changes over time 
as response to therapy of the prevalence of mutations identified in the 
baseline tumor samples. 
 Nucleic acids extracted from blood can also be used to 
investigate whether circulating tumor nucleic acids are 
associated with disease progression 


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9.2. 
Safety Analysis 
The safety analysis set includes all treated patients. 
Safety and tolerability will be monitored through continuous reporting of treatment-
emergent and treatment-related 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 NCI CTCAE v5.0. 
Physical examination, vital signs, laboratory assessments (eg, serum chemistry, 
hematology), and ECOG performance status will be monitored. All SAEs (regardless of 
relationship to IP) will be followed until resolution. Local laboratory analysis will be 
performed as per study schedule. 
9.3. 
Efficacy Analysis  
The Efficacy Analysis Set includes all enrolled patients with measurable tumor per 
RECIST v1.1 at baseline who received at least 2 doses of ABI-009 and had a follow-up 
CT / PET (or MRI). 
Efficacy will be assessed by investigators using CT / PET scans and RECIST v1.1.  Only 
RECIST v1.1 criteria will be used to assess response; PET will be used for qualitative 
purposes only. 
For the phase 2 portion of the study the primary endpoint is PF rate at 6 months. 
Progression-free rate at 6 months is the proportion of patients who are progression-free 
and alive at 6 months. The point estimate of the PF rate and the exact two-sided 95% 
confidence interval will be provided.  
Progression-free survival is defined as the time from the first day of study drug 
administration to disease progression or death due to any cause. For PFS, the KM 
estimates and corresponding two-sided 95% confidence intervals for the median and 
quartiles will be provided. The KM plot may also be provided. 
The ORR and DCR will be reported along with exact 95% confidence intervals computed 
by the Clopper-Pearson method.  
All efficacy endpoints will also be analyzed based on PTEN status. 
9.4. 
Exploratory Analysis 
Presence/level of expression of several tumor and blood biomarkers and their relationship 
to clinical responsiveness.   
9.5. 
Sample Size Considerations 
In phase 1, it is estimated that a maximum of up to 18 patients will be required to achieve 
the MTD; however, MTD could be reached with as few as 5 patients.  
In phase 2, 34-37 additional eligible patients will be enrolled at the RP2D, for a total of 40 
patients (including 3-6 patients from phase 1 at the RP2D).  Patients without follow-up 


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scans will be replaced.  Assuming a 10% attrition rate, 44 patients would need to be 
enrolled for the phase 2 portion of the study, inclusive of the phase 1 patients at RP2D. 
The focus of the phase 2 portion of the study will be on the estimation of the magnitude 
of treatment effect, as measured by PF rate at 6 months. Based on an assumed 6-month 
PF rate of 90% and a sample size of 40 patients, the 95% confidence intervals for the 6-
month PF rate will be 76.3% to 97.2%. 
9.6. 
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. 


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10. 
MONITORING, RECORDING AND REPORTING OF ADVERSE 
EVENTS  
10.1. 
Toxicities of ABI-009  
ABI-009 is an albumin-bound formulation of sirolimus. No unexpected toxicities not 
already known for sirolimus (Rapamune®) or the sirolimus prodrug, temsirolimus 
(Torisel®), were identified in the nonclinical toxicity studies, or observed in the phase 1 
studies for ABI-009. 
More details on the known precautions, warnings, and AEs of sirolimus and rapalogs are 
found in the Rapamune® and Torisel® Package Inserts (Pfizer, 2011a; Pfizer, 2011b). 
10.2. 
Toxicities of FOLFOX 
FOLFOX regimens combine oxaliplatin and leucovorin with bolus and infusional 5-
fluorouracil (5-FU). Oxaliplatin is a DNA cross-linking agent consisting of a platinum ion 
chelated with1, 2-diaminocyclohexane (DACH) and an oxalate ligand. It undergoes 
spontaneous activation in aqueous solutions via displacement of the labile oxalate ligand 
by water. The activated compounds bind with DNA, resulting in inter- and intra-strand 
platinum-DNA crosslinks. 5-FU is an anti-metabolite that blocks the methylation reaction 
of deoxyuridylic acid to thymidylic acid, causing thymidine-less cell death in rapidly 
growing cells. Leucovorin is reduced folic acid that modulates the activity of 5-FU by 
stabilizing the ternary 5-FdUMP/ thymidylate synthetase complex. Side effects associated 
with FOLFOX include neuropathy including pharyngo-laryngodysesthesia, diarrhea, 
nausea, vomiting, and mild myelosuppression. 
10.3. 
Toxicities of Bevacizumab 
Per the prescribing information, the most common adverse reactions incidence (incidence 
> 10%) are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry 
skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis 
(Genentech, 2017). 
Due to bevacizumab’s influence on blood vessels, it causes coagulative side effects and 
conversely also bleeding and wound repair problems, including GI perforation and fistulae 
(Tahover, 2013). 
10.4. 
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 


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The AE toxicity grading scale used will be the NCI CTCAE v5.0. 
10.5. 
Serious Adverse Events 
10.5.1. 
Definition of Serious Adverse Events 
An SAE is defined as an AE that meets at least 1 of the following serious criteria: 
• fatal 
• life-threatening (places the patient at immediate risk of death) 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• other medically important serious event 
An AE would meet the criterion of “requires hospitalization”, if the event necessitated an 
in-patient admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any of 
the serious criteria, the event could be classified as an SAE under the criterion of “other 
medically important serious event”.  Examples of such events could include allergic 
bronchospasm, convulsions, blood dyscrasias, drug-induced liver injury, or events that 
necessitate an emergency room visit, outpatient surgery, or urgent intervention. 
Since the criteria for the CTCAE grading scale differs from the regulatory criteria for SAEs, 
if AEs correspond to grade 4 “life threatening” CTCAE grading scale criteria 
(eg, laboratory abnormality reported as grade 4 without manifestation of life threatening 
status), it will be left to the investigator’s judgment to also report these abnormalities as 
SAEs. For any AE that applies to this situation, comprehensive documentation of the 
event’s severity status must be recorded in the patient’s medical record.   
10.5.2. 
Reporting Procedures for Serious Adverse Events 
All serious adverse experiences that are drug-related 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 Bioscience 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.   


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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 Bioscience 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 Bioscience 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 Bioscience and the IRB/EC. 
10.6. 
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 Bioscience 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 Bioscience 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 Bioscience 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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11. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND 
STUDY 
11.1. 
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. 
11.2. 
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. 


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11.3. 
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.    
Patients may be eligible for continued treatment with Aadi Bioscience’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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12. 
REGULATORY OBLIGATIONS 
12.1. 
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 Bioscience. 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.   
12.2. 
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 Bioscience before recruitment of patients into the study and shipment of Aadi 
Bioscience 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 Bioscience, in accordance with local 
procedures. 


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The investigator is responsible for obtaining annual IRB approval [IRBs only]/renewal 
[IRBs and IECs] throughout the duration of the study. Copies of the investigator’s reports 
and the IRB continuance of approval must be sent to Aadi Bioscience. 
12.3. 
Patient Confidentiality 
The investigator must ensure that the patient’s confidentiality is maintained for documents 
submitted to Aadi Bioscience. 
• 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 Bioscience, 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 Bioscience (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. 
12.4. 
Protocol Amendments   
If investigator amends the protocol, agreement from Aadi Bioscience 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 Bioscience. 
12.5. 
Termination of the Study 
Both Aadi Bioscience 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 Bioscience. 
 


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13. 
DATA HANDLING AND RECORDKEEPING 
13.1. 
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. 
13.2. 
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. 
13.3. 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including patients not receiving protocol-required therapies) as 
stipulated in the protocol for each patient in the study. For patients who withdraw prior to 
completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 2), the investigator can search publicly available records 
(where permitted) to ascertain survival status.  
This ensures that the data set(s) produced as an outcome of the study is/are as 
comprehensive as possible. 
13.4. 
The investigator is responsible 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 
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 


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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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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1. 
Study Monitoring 
The Institution representative, Aadi Bioscience representative(s) or designee 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 Bioscience representative or 
designee 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 Bioscience representative or designee 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. 
14.2. 
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 Bioscience’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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15. 
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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16. 
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