Conditions: High Grade Recurrent Glioma and Newly Diagnosed Glioblastoma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 62
Healthy volunteers: no

Brief summary:
Phase 2, open-label study of nab-sirolimus in patients with recurrent high grade glioma following prior therapy and patients with newly diagnosed glioblastoma. nab-Sirolimus was administered as single agent or in combination therapies.

Detailed description:
A phase 2, open-label study of nab-sirolimus (also known as ABI-009, nab-rapamycin, albumin-bound rapamycin) in patients with recurrent high grade glioma following prior therapy and patients with newly diagnosed glioblastoma. nab-Sirolimus was administered as single agent or in combination therapies, including temozolomide, bevacizumab, lomustine, and marizomib.

Arms:
arm 1: nab-Sirolimus (ABI-009, nab-rapamycin, albumin-bound rapamycin) was administered at 100 mg/m2 as a 30-minute IV infusion on Days 1 and 8 of every 21-day cycle. arm 2: nab-Sirolimus (60 mg/m 2 as a 30-minute IV infusion on Days 1, 8, and 15 of every 28-day cycle).

Temozolomide (PO at 50 mg/m2 daily) arm 3: nab-Sirolimus (IV 60 mg/m 2 as a 30-minute infusion on Days 1, 8, and 15 of every 28-day cycle).

Bevacizumab (IV at a fixed dose of 5 mg/kg on Days 1 and 15 of every 28-day cycle). arm 4: nab-Sirolimus was administered at 60 mg/m 2 as a 30-minute IV infusion on Days 1 and 8 of every 21-day cycle.

CCNU was administered PO at 90 mg/m2 on Day 1 of each odd 21-day cycle (ie, every 6 weeks). arm 5: nab-Sirolimus was administered at 60 mg/m 2 as a 30-minute IV infusion on Days 1, 8, and 15 of every 28-day cycle.

MRZ was administered at 0.8 mg/m 2 as a 10-minute IV infusion on Days 1, 8, and 15 of every 28-day cycle. MRZ was administered approximately 10 minutes after the end of the nab-sirolimus infusion. arm 6: Induction Treatment (4 weeks) with nab-sirolimus (60 mg/m2 IV weekly); followed by

Concomitant Treatment (standard of care; 2 cycles): nab-sirolimus (60 mg/m2 IV on Days 8 and 15 of every 21-day cycle) in combination with TMZ (75 mg/m2 PO daily for 6 weeks) + radiotherapy (30 × 200 cGy, 5 days/week); followed by

Adjuvant Treatment (6 cycles) starting 4 weeks after Concomitant Treatment, with nab-sirolimus(60 mg/m2 IV on Days 1, 8, and 15 of every 28-day cycle) in combination with TMZ (150 mg/m2 PO daily on Days 1-5 of every 28-day cycle)

Interventions: intervention 1: nab-sirolimus intervention 2: nab-sirolimus + temozolomide intervention 3: nab-sirolimus + bevacizumab intervention 4: nab-sirolimus + lomustine intervention 5: nab-sirolimus + marizomib (MRZ) intervention 6: nab-sirolimus + temozolomide + radiotherapy
Intervention descriptions: intervention 1: nab-sirolimus, single agent intervention 2: temozolomide, combination intervention 3: bevacizumab, combination intervention 4: lomustine, combination intervention 5: marizomib (MRZ), combination intervention 6: temozolomide + radiotherapy, combination

Protocol document:
Prot_SAP_001.pdf: 
 
Cover Page 
 
Study GBM-007, NCT03463265 
 
Protocol Including Statistical Analysis 
 
Last Approved Version 3.0 
Date: December 02, 2019 
 
Protocol Title 
A Phase 2, Open-label Study of ABI-009 (nab-Rapamycin) in 
Bevacizumab-naïve Patients with Recurrent High-grade 
Glioma and in Patients with Newly Diagnosed Glioblastoma 




ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
2 
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
 
Name: 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
5 
PROTOCOL SYNOPSIS 
INVESTIGATIONAL 
PRODUCT 
ABI-009, sirolimus albumin-bound nanoparticles for injectable suspension, 
nab-sirolimus, nanoparticle albumin-bound sirolimus 
TITLE 
A Phase 2, Open-label Study of ABI-009 (nab-Sirolimus) in Patients with 
Recurrent High-grade Glioma and in Patients with Newly Diagnosed 
Glioblastoma 
PROTOCOL 
NUMBER 
GBM-007 
PHASE  
Phase 2 
STUDY 
OBJECTIVES 
Arm A: Recurrent High-grade Glioma 
Primary Objective 
1. To evaluate the efficacy of intravenous (IV) ABI-009 as a single agent 
and as a combination of ABI-009 + temozolomide (TMZ), ABI-009 + 
bevacizumab (BEV), ABI-009 + lomustine (CCNU), and ABI-009 + 
marizomib (MRZ) in patients with recurrent high-grade glioma. 
Secondary Objective 
1. To evaluate the safety of ABI-009 as a single agent and in combination 
with TMZ, BEV, CCNU, or MRZ in patients with recurrent high-grade 
glioma. 
 
Arm B: Newly Diagnosed Glioblastoma (ndGBM) 
Primary Objectives 
1. To evaluate the efficacy of the combination of ABI-009 and standard 
TMZ-based chemoradiotherapy in patients newly diagnosed with 
glioblastoma. 
Secondary Objectives 
1. To evaluate the safety and efficacy of ABI-009 (Induction Treatment).  
2. To evaluate the safety of the combination of ABI-009 + TMZ + 
radiotherapy (RT) (Concomitant Treatment).  
3. To evaluate the safety of the combination of ABI-009 + TMZ (Adjuvant 
Treatment). 
 
 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
6 
Exploratory Objective for Arms A and B 
1. To evaluate tumor biomarkers related to mTOR pathway using pre-
study, archived tissue samples and if available, post-treatment tumor 
tissue samples. 
2. To evaluate blood biomarkers and correlate to outcomes. 
STUDY 
ENDPOINTS 
Primary Endpoint for Arms A and B  
Objective overall response rate (ORR, according to RANO 2010 criteria) 
Secondary Endpoints for Arms A and B 
Progression-free survival (PFS) rate at 6 months, PFS rate at 12 months, 
median PFS, overall survival (OS) at 12 months, median OS, and adverse 
events (AEs) 
Exploratory Endpoints for Arms A and B 
• Assessment of pre-treatment archived tumor samples for the activity of 
mTOR pathway and correlation with activity/tolerability 
• If available, tumor biomarkers post-progression 
• To evaluate blood biomarkers and correlate to outcomes 
STUDY DESIGN  
This is a prospective, multi-cohort, non-randomized, open-label phase 2 
study. Arm A will have 5 cohorts, aiming to determine the efficacy and safety 
profile of ABI-009 as a single agent and in combination with TMZ, BEV, CCNU, 
or MRZ in patients with recurrent high-grade glioma, who have not 
previously received any mTOR inhibitor. Arm A of the study will use Simon’s 
two-stage design for each cohort. Up to 19 patients per cohort will be 
enrolled: there will initially be 9 patients enrolled with a stopping rule that 
only if there are 2 or more positive responses will the study proceed to 
further enrollment of the next 10 patients. 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 
discretion of the patient. 
In Arm A (recurrent high-grade glioma) of the study, ABI-009 will be 
administered IV at 100 mg/m2 as a single agent on Days 1 and 8 of every 21-
day cycle (Cohort 1), or at 60 mg/m2 on Days 1, 8, and 15 of every 28-day 
cycle in combination with TMZ (50 mg/m2 PO daily), or with BEV (5 mg/kg IV 
on Days 1 and 15 of every 28-day cycle), or with MRZ (0.8 mg/m2 IV on Days 
1, 8, and 15 of every 28-day cycle), (Cohort 2, 3, and 5 respectively), or on 
Days 1 and 8 of every 21-day cycle with CCNU (90 mg/m2 on Day 1 of every 
odd cycle, Cohort 4). At the discretion of the investigator, if ABI-009 is well 
tolerated (no DLTs, dose modifications, or dose delays) at 60 mg/m2 in the 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
7 
first 3 patients in the cohort, the dose may be increased to 75 mg/m2 for 
subsequent patients in the cohort.  
Arm B (ndGBM) of the study will evaluate the efficacy of ABI-009 induction 
therapy (60 mg/m2 IV every week for 4 weeks) followed by the combination 
of ABI-009 (60 mg/m2 IV on Days 8 and 15 of every 21-day cycle for 2 cycles) 
with the standard of care treatment of TMZ (75 mg/m2 PO daily for 6 weeks) 
+ RT (30x 200 cGy, 5 days/week) (Concomitant Treatment) followed by ABI-
009 (60 mg/m2 IV on Days 1, 8, and 15 of every 28-day cycle for 6 cycles) + 
TMZ (150 mg/m2 PO daily on Days 1-5 of every 28-day cycle for 6 cycles) 
(Adjuvant Treatment) in patients with ndGBM who can have either non-
measurable disease or enhancing tumors after surgery and have not 
previously received any local or systemic therapy. Up to 19 patients will be 
enrolled in Arm B.  
NUMBER OF 
PATIENTS 
Arm A (recurrent high-grade glioma): up to 95 response-evaluable patients 
will be enrolled (up to 19 per cohort; 5 cohorts).  
Arm B (ndGBM): up to 19 response-evaluable patients will be enrolled. 
SAMPLE SIZE 
ESTIMATE 
Simon's two-stage design (Simon, 1989) will be used for Arm A of this 
study. The null hypothesis that the true response rate is 15% will be tested 
against a one-sided alternative. In the first stage, 9 patients will be 
accrued. If there are 1 or fewer responses in these 9 patients, the study 
will be stopped. Otherwise, 10 additional patients will be accrued for a 
total of 19. The null hypothesis will be rejected if 6 or more responses are 
observed in 19 patients. This design yields a type I error rate of 0.0497 and 
power of 0.8132 when the true response rate is 40%. 
INCLUSION 
CRITERIA 
Inclusion Criteria Common for Both Arms A and B 
A patient will be eligible for inclusion in this study only if all the following 
criteria are met: 
1. Understand and voluntarily sign and date an informed consent 
document prior to any study related assessments/procedures. 
2. Males and females of age ≥18 years at the time of signing the informed 
consent document. 
3. Karnofsky Performance Status (KPS) score ≥70% (see Appendix 1. 
Karnofsky Performance Status). 
4. No investigational agent within 4 weeks prior to the first dose of study 
drug. 
5. All AEs resulting from prior therapy and surgery must have resolved to 
National Cancer Institute Common Terminology Criteria for Adverse 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
8 
Events (NCI-CTCAE) v5.0 grade ≤1 (except for laboratory parameters 
outlined below). 
6. Adequate hematological, renal, and hepatic function (assessment 
performed within 14 days prior to study treatment): 
- 
Absolute neutrophil count (ANC) ≥1.5 x 109/L 
- 
Platelets ≥100 x 109/L 
- 
Hemoglobin ≥9 g/dL.  
Serum creatinine ≤1.5 x upper limit of laboratory normal (ULN); 
Total serum bilirubin ≤1.5 x ULN, or ≤3 x ULN if Gilbert’s disease 
is documented 
− 
Aspartate Serine Transaminase (AST), Aspartate Leucine 
Transaminase (ALT), Alkaline Phosphatase (ALP) ≤2.5 x ULN 
− 
Serum triglyceride <300 mg/dL; serum cholesterol <350 mg/dL 
7. Patients must be without seizures for at least 14 days prior to 
enrollment, and patients who receive treatment with anti-epileptic 
drugs (AEDs) must be on stable doses for at least 14 days prior to 
enrollment. Patients must be off enzyme-inducing anti-epileptic drugs 
(EIAEDs) for at least 14 days prior to enrollment and cannot be on EIAEDs 
at any time during the study. 
8. Steroid therapy for control of cerebral edema is allowed at the discretion 
of the Investigator. Patients should be on stable or decreasing dose of 
corticosteroids for at least 1 week prior to the first dose of study drug.  
9. 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.  
• 
Male patients with partners of child-bearing potential must agree 
to take contraceptive measures for the duration of treatment 
and for 3 months after the last study treatment. 
10. Willing and able to adhere to the study visit schedule and other protocol 
requirements. 
 
Inclusion Criteria Specific for Arm A 
1. All patients must have histologic evidence of high grade glioma (World 
Health Organization [WHO] grade 3 or grade 4) and radiographic 
evidence of recurrence or disease progression (defined as either a 
greater than 25% increase in the largest bi-dimensional product of 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
9 
enhancement, a new enhancing lesion, or a significant increase in T2 
FLAIR). Patients must have at least 1 measurable lesion by RANO criteria 
(≥10 mm in 2 perpendicular diameters). 
2. Patients must have previously failed a treatment regimen, including 
radiation and/or chemotherapy. 
3. No prior treatment with mTOR inhibitors.  
4. No prior treatment with TMZ for the treatment of recurrent glioma for 
patients entering the ABI-009 + TMZ cohort. 
5. No prior treatment with BEV or any other anti-angiogenic agents, 
including sorafenib, sunitinib, axitinib, pazopanib, or cilengitide, for 
patients entering the ABI-009 + BEV cohort. 
6. No prior treatment with CCNU for the ABI-009 + CCNU arm. 
7. No prior treatment with MRZ or any other proteasome inhibitors, 
including bortezomib (BTZ), carfilzomib (CFZ), or ixazomib (IXZ), for 
patients entering the ABI-009 + MRZ cohort. 
8. At least 4 weeks from surgical resection and at least 12 weeks from the 
end of RT prior to enrollment in this study, unless relapse is confirmed 
by tumor biopsy or new lesion outside of radiation field, or if there are 2 
magnetic resonance imaging (MRI) scans confirming progressive disease 
(PD) that are approximately 4 weeks apart. 
 
Inclusion Criteria Specific for Arm B 
1. Histologically confirmed ndGBM. 
2. Patients must have had surgery and can have either non-measurable 
disease or a measurable post-contrast lesion after surgery detected by 
MRI.  
3. No prior treatment with mTOR inhibitors, and no prior local or systemic 
therapy for GBM.  
EXCLUSION 
CRITERIA 
Exclusion Criteria Common for Both Arms A and B 
A patient will not be eligible for inclusion in this study if any of the following 
criteria apply: 
1. Co-medication or concomitant therapy that may interfere with study 
results, including anti-coagulants and enzyme-Inducing anti-epileptic 
drugs (EIAEDs).   
2. History of thrombotic or hemorrhagic stroke or myocardial infarction 
within 6 months. 
3. Pregnant or breast feeding. 
4. Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection requiring IV antibiotics & psychiatric illness/social 
situations that would limit compliance with study requirements, or 
disorders associated with significant immunocompromised state. 
5. Active gastrointestinal bleeding. 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
10 
6. Uncontrolled hypertension (systolic blood pressure ≥160 mm Hg and/or 
diastolic blood pressure ≥90 mm Hg. 
7. Patients with history of intestinal perforations, fistula, hemorrhages 
and/or hemoptysis ≤6 months prior to first study treatment. 
8. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite 
adequate therapy. 
9. Patients with history of interstitial lung disease and/or pneumonitis, or 
pulmonary hypertension.  
10. Use of strong inhibitors and inducers of CYP3A4 (such as EIAEDs 
including carbamazepine, phenytoin, oxcarbazepine, topiramate, among 
others) 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.  
11. Known other previous/current malignancy requiring treatment within ≤ 
3 years except for limited disease treated with curative intent, such as in 
situ prostate cancer, intracapsular renal cancer, cervical carcinoma in 
situ, squamous or basal cell skin carcinoma, and superficial bladder 
carcinoma.  
12. Any comorbid condition that restricts the use of study drug and 
confounds the ability to interpret data from the study as judged by the 
Investigator or Medical Monitor.  
13. Known infection with human Immunodeficiency Virus (HIV), or active 
Hepatitis B or Hepatitis C. 
DURATION OF 
TREATMENT AND 
STUDY 
PARTICIPATION  
The Arm A of this study is expected to take approximately 32 months from 
first patient enrolled to last patient follow-up, including approximately 24 
months of enrollment period, an estimated 6 months of treatment (or until 
unacceptable toxicity or disease progression) and an end of treatment visit 
(EOT) within 4 weeks after last treatment. 
The Arm B of this study is expected to take approximately 24 months from 
first patient enrolled to last patient follow-up, including approximately 16 
months of enrollment period, up to 12 months of treatment (or until 
unacceptable toxicity or disease progression) and an EOT within 4 weeks 
after last treatment. 
End of Treatment 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 
4 weeks after the last dose of ABI-009. 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
11 
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 on-study 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 
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 
Arm A (recurrent high-grade glioma):  
Cohort 1: ABI-009 
ABI-009 will be administered at 100 mg/m2 as a 30-minute IV infusion on 
Days 1 and 8 of every 21-day cycle. Two dose reduction levels will be allowed 
for toxicities: 75 mg/m2 and 60 mg/m2. 
Cohort 2: ABI-009 + TMZ 
ABI-009 will be administered at 60 mg/m2 as a 30-minute IV infusion on Days 
1, 8, and 15 of every 28-day cycle. If ABI-009 is well tolerated at 60 mg/m2 in 
the first 3 patients in the cohort, the dose may be increased to 75 mg/m2. 
Three dose reduction levels will be allowed: 45, 30, and 20 mg/m2. 
Temozolomide will be administered PO at 50 mg/m2 daily. 
Cohort 3: ABI-009 + BEV 
ABI-009 will be administered intravenously at 60 mg/m2 as a 30-minute 
infusion on Days 1, 8, and 15 of every 28-day cycle. If ABI-009 is well 
tolerated at 60 mg/m2 in the first 3 patients in the cohort, the dose may be 
increased to 75 mg/m2. Three dose reduction levels will be allowed: 45, 30, 
and 20 mg/m2.  
Bevacizumab will be administered as an IV infusion (90 minutes 1st dose, 60 
minutes 2nd dose, and 30 minutes afterward assuming tolerability) at a fixed 
dose of 5 mg/kg on Days 1 and 15 of every 28-day cycle. Bevacizumab will 
be administered approximately 10 minutes after the end of the ABI-009.  
Cohort 4: ABI-009 + CCNU 
ABI-009 will be administered at 60 mg/m2 as a 30-minute IV infusion on Days 
1 and 8 of every 21-day cycle. If ABI-009 is well tolerated at 60 mg/m2 in the 
first 3 patients in the cohort, the dose may be increased to 75 mg/m2. Three 
dose reduction levels will be allowed: 45, 30, and 20 mg/m2. 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
12 
Lomustine (CCNU) will be administered PO at 90 mg/m2 on Day 1 of each 
odd 21-day cycle (ie, every 6 weeks). 
Cohort 5: ABI-009 + MRZ 
ABI-009 will be administered at 60 mg/m2 as a 30-minute IV infusion on Days 
1, 8, and 15 of every 28-day cycle. If ABI-009 is well tolerated at 60 mg/m2 in 
the first 3 patients in the cohort, the dose may be increased to 75 mg/m2. 
Three dose reduction levels will be allowed for toxicities: 45, 30, and 20 
mg/m2.  
MRZ will be administered at 0.8 mg/m2 as a 10-minute IV infusion on Days 
1, 8, and 15 of every 28-day cycle. MRZ will be administered approximately 
10 minutes after the end of the ABI-009 infusion.   
For Arm A, patients will continue to receive 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 discontinue combination agents may remain on 
study receiving ABI-009 in the absence of disease progression or toxicity. 
Patients will be enrolled sequentially from Cohort 1 through 5 in groups of 3 
patients. After the enrollment of 3 patients in the previous cohort, 
enrollment in subsequent cohorts can start. If a patient is not eligible for 
enrollment into the next cohort due to prior exposure to therapy, he/she is 
allowed to be enrolled in a subsequent cohort if the patient meets all other 
inclusion criteria. If the drug supply to a cohort is delayed or limited, an 
eligible patient can be enrolled into the next cohort. 
Arm B (ndGBM):  
Induction Treatment: ABI-009 
Induction Treatment will start at least 3-8 weeks following surgical resection 
of ndGBM and after the surgical wound is fully healed. ABI-009 will be 
administered IV at 60 mg/m2 as a 30-minute IV infusion every week for 4 
weeks. Three dose reduction levels will be allowed: 45, 30, and 20 mg/m2. 
Concomitant Treatment: ABI-009 + TMZ + RT 
Concomitant Treatment will start 1 week after the completion of Induction 
Treatment and will last for 6 weeks (2 cycles). ABI-009 will be administered 
IV at 60 mg/m2 as a 30-minute IV infusion on Days 8 and 15 of every 21-day 
cycle. Three dose reduction levels will be allowed: 45, 30, and 20 mg/m2. 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
13 
Temozolomide will be administered at 75 mg/m2 PO daily for 6 weeks. Focal 
RT will be given daily at 30x 200 cGy, 5 days/week for a total dose of 60 Gy 
(or equivalent regimens as per RTOG guidelines). 
Adjuvant Treatment: ABI-009 + TMZ 
Adjuvant Treatment will start 4 weeks after the completion of Concomitant 
Treatment and will last for 24 weeks. ABI-009 will be administered IV at 60 
mg/m2 as a 30-minute IV infusion on Days 1, 8, and 15 of every 28-day cycle 
for 6 cycles. Three dose reduction levels will be allowed: 45, 30, and 20 
mg/m2. 
Temozolomide will be administered at 150 mg/m2 PO daily on Days 1-5 of 
every 28-day cycle for 6 cycles. In the absence of toxicity, TMZ may be 
administered at 200 mg/m2/day starting in Cycle 2. 
KEY EFFICACY 
ASSESSMENTS 
All patients with measurable tumor per RANO 2010 criteria (see  
Appendix 2. Response Assessment for Neuro-Oncology (RANO)) at baseline 
who received at least 2 doses of ABI-009 and had a follow-up MRI will be 
evaluated for efficacy. 
Arm A (recurrent high-grade glioma):  
Tumor response, including complete response (CR), partial response (PR), 
stable disease (SD), or PD, will be assessed with MRI using the RANO 2010 
criteria, including: 
• Radiographic Response Rate  
• PFS, PFS at 6 months, PFS at 12 months 
Overall Survival will be recorded, and OS at 12 months will be calculated. 
For Cohorts 1 and 4, MRI will be done every 6 weeks; for Cohorts 2, 3 and 5, 
MRI is every 8 weeks. 
 
Arm B (ndGBM): 
Tumor response will be assessed with MRI imaging on Day 1 and 4 weeks (±7 
days)  after the end of Concomitant Treatment and prior to the start of 
Adjuvant Treatment, and then every 8 weeks (±7 days) during Adjuvant 
Treatment until disease progression. 
For both Arms A and B, the primary endpoint of ORR will be determined by 
a local radiologist(s).  
After disease progression, patients will be followed for survival every 12 
weeks, or more frequently as needed, until death, withdrawal of consent, or 
the study closes, whichever is the earliest.  


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432   
 
 
 
Confidential and Proprietary 
14 
The primary endpoint is ORR by independent radiologic review and is 
defined as the proportion of patients who achieve a confirmed PR or CR 
per RANO 2010 criteria. PFS at 6 months, PFS at 12 months, median PFS, 
OS at 12 months, and median OS will be summarized using Kaplan-Meier 
(KM) analysis. Quartiles with 95% CIs will be summarized.  
KEY SAFETY 
ASSESSMENTS 
All patients will be evaluated for safety analysis if they receive at least 1 dose 
of ABI-009. 
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 investigational product (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, following NCI-CTCAE 
v5.0. 
Physical examination, vital sign, KPS, and laboratory assessments will be 
monitored frequently as needed throughout the treatment cycles (eg, serum 
chemistry at Day 1 of every cycle, hematology at every treatment visit). All 
serious AEs (SAEs) (regardless of relationship to IP) will be followed until 
resolution. Laboratory analysis will be performed as per study schedule. 
The treated population (Full Analysis Set) will be the analysis population for 
all safety analyses. Adverse events will be grouped by their system organ 
class and preferred term. Summary tables will include the number and 
percentage of patients with AEs, SAEs, fatal AEs and other AEs of interest. 
 














ABI-009  
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
Confidential and Proprietary 
21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AED 
anti-epileptic drug 
ALP 
alkaline phosphatase  
ALT 
alanine transaminase (SGPT) 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (SGOT) 
AUC 
area under the time-concentration curve 
β-hCG 
beta human chorionic gonadotropin 
BBB 
blood-brain barrier 
BCNU 
carmustine 
BEV 
bevacizumab 
BSA 
body surface area 
BTZ 
bortezomib 
Cmax 
maximum plasma drug concentration 
CBC 
complete blood count 
CCNU 
lomustine 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiography 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EIAED 
enzyme-inducing anti-epileptic drug 
EOS 
end of study 
EOT 
end of treatment 
FDA 
Food and Drug Administration 


ABI-009  
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
Confidential and Proprietary 
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GBM 
glioblastoma 
GCP 
Good Clinical Practice 
G-CSF
granulocyte-colony stimulating factor 
HGG
high-grade glioma 
HIV
human Immunodeficiency Virus 
HUVEC
human umbilical vein endothelial cells 
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee 
IHC
Immunohistochemistry 
IND
investigational new drug  
INR
international normalised ratio 
IP
investigational product 
IRB
Institutional Review Board 
IV
intravenous 
KM
Kaplan-Meier 
KPS
Karnofsky Performance Status 
mg
milligram 
mL
milliliter 
MRI
magnetic resonance imaging 
MRZ
marizomib 
MTD
maximum-tolerated dose 
mTOR
mammalian target of rapamycin 
nab
nanoparticle albumin-bound 
ndGBM
newly diagnosed glioblastoma 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 


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PO 
orally 
PR 
partial response 
PT 
prothrombin time 
PTEN 
protein tyrosine phosphatase 
PTT 
partial thromboplastin time 
RANO 
Response Assessment in Neuro-Oncology Criteria 
rGBM 
recurrent glioblastoma 
RT 
radiotherapy 
RTOG 
Radiation Therapy Oncology Group 
SAE 
serious adverse event 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
T2-FLAIR 
T2-weighted-Fluid-Attenuated Inversion Recovery 
TBL 
total bilirubin level 
TMZ 
temozolomide 
TTFields 
alternating electric fields therapy 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 


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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 combination agent 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 4 
weeks of the last dose of ABI-009 or combination agent, whichever 
is later.  
Follow-up Period 
 
The 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 RANO 2010 criteria 
at baseline who received at least 2 doses of ABI-009 and had a follow-
up MRI (or CT) (modified treated population). 
Safety Analysis Set 
All enrolled patients who receive at least 1 dose of ABI-009 (treated 
population). 
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. 


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Overall response rate 
 
The proportion of patients who achieve a confirmed partial response 
or complete response per RANO 2010 criteria. 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 RANO or death due to any 
cause, whichever comes first.  
 
 


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1. 
INTRODUCTION 
1.1. 
Glioma and Glioblastoma 
Gliomas start in the glial cells of the brain or the spine and comprise about 30% of all brain and 
central nervous system tumors, and 80% of all malignant brain tumors (Goodenberger, 2012). 
High-grade gliomas (HGG) are either World Health Organization (WHO) grade 3 or grade 4 tumors 
and tend to grow rapidly and spread faster than tumors of a lower grade. The most common 
grade 3 tumor is anaplastic astrocytoma and the most common grade 4 tumor is glioblastoma 
(GBM). Other HGGs include anaplastic oligodendroglioma and pleiomorphic xanthoastrocytoma 
(Bouffet, 2009; Louis, 2016).  
Glioblastoma remains a deadly disease with currently limited treatment options. The median 
survival is only 15 months from initial diagnosis for patients with newly diagnosed GBM (ndGBM), 
with a 2-year survival rate of 27% and 5-year survival rate less than 5% (Stupp, 2005; Khosla, 
2016). For ndGBM, currently the standard-of-care treatment strategy is surgical resection 
followed by radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ). Additional 
treatment options are to insert a carmustine (BCNU) wafer at surgery or adding electrical fields 
at the time of adjuvant TMZ. Alternating electric fields therapy (TTFields) is another treatment 
option that has been approved by the Food and Drug Administration (FDA) to use in combination 
with TMZ adjuvant treatment (National Comprehensive Cancer Network, 2016). 
After first-line treatment, almost all GBM patients will relapse within 9 months of initial 
treatment (Stupp, 2012). For patients with recurrent GBM (rGBM), the median survival is only 
about 7 months (Gallego, 2015). An effective treatment strategy is yet to be established for rGBM 
patients. There are currently 3 FDA approved treatment options for rGBM: carmustine wafer, 
TTFields, and bevacizumab (BEV) (National Comprehensive Cancer Network, 2016). Bevacizumab 
has only gained accelerated approval based on overall response rate (ORR) and progression-free 
survival (PFS) in 2 phase 2 studies but has not shown a clear improvement in overall survival (OS) 
(Genentech, 2016). When used in randomized controlled trials as a treatment in patients with 
rGBM, BEV alone resulted in median OS of 7 to 9 months, similar to historical data reported with 
chemotherapies (Friedman, 2009; Kreisl, 2009; Taal, 2014; Field, 2015). Therefore, there is a clear 
need for novel treatment options for this devastating disease. 
1.2. 
mTOR 
mTOR is a serine/threonine-specific protein kinase, downstream of the phosphatidylinositol 3-
kinase (PI3K)/Akt (protein kinase B) pathway, and a key regulator of cell survival, proliferation, 
stress, and metabolism. Additionally, mTOR is involved in regulating angiogenesis by controlling 
endothelial and smooth muscle cell proliferation via the hypoxia-inducible factor-1α and vascular 
endothelial growth factor (Corradetti, 2006). Sirolimus and its analogs (rapalogs), including 
everolimus and temsirolimus, 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, an oral therapeutic, is an efficacious mTOR inhibitor, it has poor solubility, 
low oral bioavailability, and dose-limiting toxicity (DLT) (O'Donnell, 2008; Yuan, 2009).  
 


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Consistent with its role in cell proliferation, the mTOR pathway is frequently over activated in 
multiple human malignancies including GBM and is thus considered to be an attractive target for 
anticancer therapy. Activation of PI3k/Akt pathway has been frequently found in GBM patients 
and is associated with reduced survival (Chakravarti, 2004). PI3K/Akt/mTOR pathway activation 
can occur by ligand binding to the extracellular domain of receptor tyrosine kinases such as 
epidermal growth factor receptor (EGFR), which is amplified or mutated in 40% to 60% of GBM 
(Hurtt, 1992). Furthermore, alterations in the PTEN tumor suppressor gene, including PTEN 
mutations/deletions which occur in 30% to 40% of GBM patients, can also result in pathway 
activation (Wang, 1997). In in vitro experiments, glioma cell lines were among the most sensitive 
to the effect of temsirolimus. In vivo studies demonstrated activity of temsirolimus against 
subcutaneous and orthotopic GBM models in nude mice. Preclinical studies have shown that 
everolimus and temsirolimus have poor brain penetration, limiting their potential use for the 
treatment of GBM (EMEA, 2007; O'Reilly, 2010). 
In a phase 2 study in 100 patients with newly diagnosed ndGBM, the combination of oral 
everolimus at 70 mg 1x weekly during and after conventional TMZ-based chemoradiotherapy 
resulted in moderate toxicity, with 57% of patients having at least 1 grade 3+ adverse event (AE) 
and 23% of patients having a grade 4 AE, with the most common events being thrombocytopenia 
(18%) and neutropenia (16%) (Ma, 2015). Grade 3 or 4 nonhematologic events were observed in 
45 patients, and 21 patients had at least 1 grade 4 nonhematologic AE. The most common grades 
3–4 nonhematologic events were fatigue (11%) and hypercholesterolemia (9%). Twenty-two 
patients terminated therapy early because of an AE. One patient died due to neutropenia and 
sepsis. Combined everolimus/chemoradiotherapy was not associated with prolonged survival 
compared with historical controls. Patients in this study had a 12-month OS rate of 64%, a median 
OS of 15.8 months (95% CI: 13.0, 20.3), and a median PFS of 6.4 months (95% CI: 5.4, 9.0).  
In a phase 2 study of temsirolimus in 43 patients with rGBM (Chang, 2005), temsirolimus was 
administered at 250 mg weekly to patients on enzyme-inducing anti-epileptic drugs (EIAEDs) and 
at 250 mg and later 170 mg weekly to patients not on EIAEDs. Overall, temsirolimus was well 
tolerated, with no grade 4 hematological toxicities and no toxic death.  The major toxicities 
observed were elevation in lipid profiles, lymphopenia, and stomatitis. There was no evidence of 
efficacy with temsirolimus as a single agent, with 1 patient progression-free at 6 months. Of the 
patients assessable for response, there were 2 partial responses and 20 with stabile disease (SD). 
The median time to progression was 9 weeks. 
In a separate phase 2 study of temsirolimus in 65 patients with rGBM (Galanis, 2005), 
temsirolimus administered at 250 mg weekly was well tolerated. The incidence of grade 3 or 
higher nonhematologic toxicity was 51%, and consisted mostly of hypercholesterolemia (11%), 
hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed 
in 11% of patients. There was no objective response with temsirolimus as a single agent but 36% 
of patients showed evidence of improvement in neuroimaging. Progression-free survival at 6 
months was 7.8% and median OS was 4.4 months. 
1.3. 
ABI-009  
ABI-009 (nab-sirolimus) is a nanoparticle form of human albumin-bound sirolimus with a mean 
particle size of approximately 100 nm developed with a proprietary nanoparticle albumin-bound 


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(nab®) technology. ABI-009 is freely dispersible in saline and is suitable for intravenous (IV) 
administration and has produced both a favorable safety profile and evidence of efficacy in 
patients with metastatic solid tumors (Gonzalez-Angulo, 2013). 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, making it 
an ideal candidate for drug delivery (Kremer, 2002; Kratz, 2008). Importantly, albumin has been 
shown to be able to penetrate the blood-brain barrier (BBB) and highly accumulate in GBM. 
Intravenous administration of 5-aminofluorescein-labeled albumin prior to surgery resulted in 
the fluorescent visualization of malignant gliomas, which facilitated the complete resection of 
fluorescent tumor tissue (Kremer, 2009). In an orthotopic mouse GBM xenograft model, albumin-
linked aldoxorubicin but not doxorubicin significantly delayed tumor growth and prolonged 
survival. In a phase 2 study of patients with rGBM, aldoxorubicin treatment resulted in 3 partial 
response (PR), 7 SD, and 11 progressive disease (PD) according to magnetic resonance imaging 
(MRI) among 21 patients (Groves, 2016). In a biodistribution study in rats, radiolabeled ABI-009 
showed significant brain uptake at 5 days (Aadi internal data). Therefore, albumin may facilitate 
the efficient delivery of nab-sirolimus into GBM tumors, making it a useful treatment option for 
GBM. 
1.3.1. 
ABI-009 Preclinical Pharmacology, Pharmacokinetics, and Toxicity 
Preclinical primary pharmacology studies in vivo demonstrated significant antitumor activity of 
ABI-009 as a single agent administered IV at 40 mg/kg, 3 x weekly for 4 weeks, across different 
tumor xenograft models in nude mice, including breast, colorectal, multiple myeloma, 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). In addition, recent preclinical study has demonstrated that combination of ABI-
009 with the Akt inhibitor perifosine induced synergistic antitumor activity in multiple myeloma 
(Cirstea, 2010). 
Preclinical pharmacokinetic (PK) studies in rats showed that intravenously administered ABI-009 
exhibited linear PK with respect to dose and large volume of distribution, 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 
literature of sirolimus (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 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 four 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 (Novartis Pharmaceuticals Corporation, 
2014; Wyeth Pharmaceuticals Inc., 2015; Wyeth Pharmaceuticals Inc., 2017). Refer to the 
Investigators’ Brochure of ABI-009 for more detailed preclinical safety information.  


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1.3.2. 
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 administered intravenously per week for 3 weeks, 
followed by a week of rest (28-day cycle, qw3/4). Two dose-limiting toxicities of grade 3 AST 
increase and grade 4 thrombocytopenia occurred in the 150 mg/m2 cohort, and 2 DLTs of grade 
3 suicidal ideation and grade 2 hypophosphatemia occurred in the 125 mg/m2 cohort. The 
maximum tolerated dose (MTD) was established at 100 mg/m2. 
Nineteen patients were evaluable for efficacy. One patient in the 45 mg/m2 (95 mg actual 
sirolimus dose) cohort, diagnosed with adenocarcinoma of the kidney and with bone and 
intrathoracic metastases, had a confirmed PR. The target lesion of this patient was reduced by 
35.1% and the duration of response lasted 183 days. Two (11%) patients (at doses 45 and 125 
mg/m2, with actual sirolimus doses of 88 mg and 193 mg, respectively) had an overall tumor 
evaluation of confirmed SD: 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 AEs requiring a week dose delay.  
ABI-009 produced a fairly dose proportional increase of maximum concentration (Cmax) and area 
under the curve (AUC) across the dose range tested, and it significantly inhibited mTOR targets 
S6K and 4EBP1. 
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 


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therapeutics and a trial in patients with advanced STS is currently evaluating the combination of 
ABI-009 and nivolumab (NCT03190174). 
1.4. 
Marizomib 
The proteasome is a central cellular structure for the turnover of proteins. Cancer cells often 
exhibit enhanced proteasome activity and inhibition of proteasome activity may preferentially 
affect the viability of cancer cells, including high grade glioma (Crawford, 2011; Bota, 2016). 
Marizomib (MRZ), also known as Salinosporamide A (NPI-0052), is an irreversible inhibitor of the 
20S proteasome (Chauhan, 2005; Groll, 2006). MRZ is currently in development for the treatment 
of newly diagnosed and recurrent glioblastoma, as well as other cancers by Celgene Corporation.  
1.4.1. 
Clinical Experience with Marizomib 
As of 10 Jul 2019, a total of 611 patients have received one or more doses of MRZ in 1 phase 3 
study and 7 Phase 1 or Phase 1/2, dose-escalation, clinical studies evaluating MRZ as a single 
agent or in combination with other anticancer drugs.  
Safety 
In MRZ-108 (for completed Parts 1, 2, and 3) in recurrent glioblastoma (rGBM), at MRZ doses up 
to 0.8 mg/m2 in the combination arm with BEV (n = 67), the most common treatment-emergent 
adverse events (TEAEs) were fatigue, nausea, vomiting, headache, hallucination, confusional 
state, hypertension, dizziness, fall, ataxia, diarrhea,  dysphonia, and gait disturbance. The most 
common TEAEs reported in the 0.8 mg/m2 monotherapy arm (n = 30) were fatigue, headache, 
hallucination, insomnia, nausea, vomiting, constipation, ataxia, hypokalemia, hyperglycemia, 
confusional state, diarrhea, dysarthria, platelet count decreased, and aphasia. The majority of 
Grade 3 and higher TEAEs occurred in the system organ classes (SOCs) of nervous system 
disorders, psychiatric disorders, and vascular disorders.  
As expected, based on preclinical and earlier clinical studies, MRZ crosses the BBB leading to CNS 
AEs in more than 80% of patients in combination and in monotherapy including the special 
interest CNS AEs of hallucinations, ataxia, dizziness, dysarthria, fall, and gait disturbances. These 
CNS AEs are manageable with dose modification and supportive treatment as required. In 
addition, infusion site reactions were observed in 20% of patients in monotherapy and in 27% of 
patients in combination therapy at MRZ doses up to 0.8 mg/m2; however, the incidence of events 
decreased over the course of the study with placement of central or peripherally inserted central 
catheter (PICC) lines as deemed necessary. Treatment-emergent AEs leading to permanent 
discontinuation of MRZ were observed in 3% of patients for monotherapy and in 12% of patients 
in combination therapy at MRZ doses up to 0.8 mg/m2. The safety profile of this treatment in 
rGBM appears consistent with the individual agents and relatively safe in this population with 
limited treatment options. 
In the ongoing Study MRZ-112 in ndGBM, available data with doses ranging from 0.55 mg/m2 to 
1.0 mg/m2 of MRZ (n = 66) indicate that the safety profile is similar to the safety in the recurrent 
GBM study, with the most common TEAEs for the whole treatment period reported as  fatigue, 
nausea, hallucination, vomiting, headache,  confusional state, constipation, and gait disturbance. 
Grade ≥3 TEAEs occurred most frequently in the SOCs of nervous system disorders, general 


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disorders and administration site conditions, psychiatric disorders, and gastrointestinal 
disorders. Special interest CNS AEs occurred in 80.3% of patients and are similar to those 
observed in rGBM and manageable with the protocol outlined dose modifications and with 
supportive treatment. Infusion site reactions have occurred in 28.8% of patients. Treatment 
emergent AEs leading to permanent discontinuation of MRZ were observed in 21.2% of patients. 
Based on the available safety data in Study MRZ-112, MRZ in combination with TMZ/RT and 
followed by TMZ in patients with ndGBM, appears to be safe and tolerable at the studied doses 
and warrants continued clinical development in the first line setting. 
In summary, toxicities associated with IV MRZ in both recurrent and newly diagnosed GBM have 
been manageable, with most AEs attenuated following dose reduction and reversible upon 
discontinuation of the drug. Refer to Marizomib Investigator’s Brochure (Edition 13.0, dated Oct 
4, 2019) for further information. 
Efficacy 
Study MRZ-108 
Study MRZ-108 is a 4-part, open-label, combination study of MRZ and bevacizumab and of MRZ 
alone in patients with recurrent WHO Grade IV GBM. Part 1, Phase 1 of this study is a dose-
escalation and dose-expansion study with MRZ in combination with BEV. Part 2, Phase 2 of this 
study evaluates MRZ used as a single agent. Part 3, Phase 2 of the study evaluates intrapatient 
dose escalation of MRZ in combination with BEV. Part 4, Phase 1 of the study was added to 
evaluate the feasibility of enterally administered MRZ. 
In Parts 1, 2 and 3, 107 patients (36, 30, and 41 patients, respectively) with rGBM were enrolled 
and all 107 patients have discontinued treatment. Part 4 of the study is ongoing with 14 patients 
enrolled.  No efficacy data is available. 
Overall, the combination of MRZ + BEV has demonstrated encouraging clinical activity. The best 
overall Response Assessment in Neuro-Oncology (RANO) criteria response, as determined by the 
investigators, for the 67 patients in Parts 1 and 3 up to the 0.8 mg/m2 dose included: 2 complete 
responses (CR), 21 partial responses (PR), and 25 stable disease (SD) with an overall response 
rate (ORR) of 34.3%. The 6-month progression-free survival (PFS) rate was 29.8% and the median 
overall survival (OS) was 9.1 months (95% confidence interval [CI] 6.3 to 10.9 months). 
Fifteen response-evaluable patients were enrolled to receive MRZ monotherapy in the first stage 
of MRZ-108 Part 2. One confirmed PR was observed in these 15 patients and the clinical study 
was expanded to enroll an additional 15 patients. None of the subsequently enrolled 15 patients 
had an objective response by RANO criteria. All 30 patients discontinued study treatment due to 
disease progression (28), patient decision (1), and for other reasons (1). While only 1 patient had 
a confirmed PR, 8 patients (26.7%) had SD (duration ranging from 0.7 to 9.5 months for 7 patients; 
1 patient discontinued prior to progressive disease [PD]). Single agent activity with MRZ was also 
noted in 4 patients, including the 1 patient with a confirmed PR, and 3 patients with durable 
clinical stabilization. Two more patients were determined to have little or no tumor present upon 
subsequent surgery, supporting the observation of possible pseudoprogression with single-agent 
MRZ treatment; these 2 patients were assessed to have PD (per RANO criteria) prior to 
undergoing subsequent surgery. 


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Study MRZ-112 
Study MRZ-112 is an ongoing Phase 1b study of MRZ in combination with TMZ/RT followed by 
TMZ in patients with ndGBM. During the dose escalation part of the study, patients are enrolled 
in parallel to the concomitant treatment arm (TMZ/RT + MRZ) and the adjuvant treatment arm 
(TMZ + MRZ). The study was amended to include a cohort of patients treated with the tumor 
treating fields device, Optune®, in combination with adjuvant MRZ and TMZ treatment. 
Preliminary data from 10 Jul 2019 show a median OS of 14.5 months for patients enrolled in the 
concomitant treatment arm up to 0.8 mg/m2. The 9-month PFS and 12-month OS rates are 35.5% 
and 54.3%, respectively. In patients who started in the adjuvant treatment arm in doses up to 0.8 
mg/m2 the median OS is 30.2 months. The 9-month PFS and 12-month OS rates are 45.5% and 
72.7%, respectively. Refer to Marizomib Investigator’s Brochure (Edition 13.0, dated Oct 4, 2019) 
for further information. 
1.5. 
 Rationale for Study Combinations  
1.5.1. 
Rationale for Investigating ABI-009 
Clinically, ABI-009 has unique characteristics amongst the available mTOR inhibitors. ABI-009 
produced a fairly dose proportional increase of Cmax and AUC across the dose range tested, and 
it significantly inhibited mTOR targets S6K and 4EBP1. The PK profile of sirolimus administered as 
ABI-009 is categorically different from those of the other oral or IV administered mTOR inhibitors. 
Intravenous infusion of ABI-009 from 45 to 150 mg/m2 results in high Cmax of sirolimus upon 
administration followed by a long half-life of approximately 60 hrs that allows once weekly 
dosing. Peak levels of sirolimus after ABI-009 are well above 1000 ng/mL range that may have 
significant tumor penetration effect. Oral mTOR inhibitors such as sirolimus or everolimus have 
poor absorption with a high inter- and intra-patient variability and a poor safety profile that 
requires low basal levels (low ng/mL level) to be maintained over the course of treatment. 
Temsirolimus on the other hand is a prodrug of sirolimus (sirolimus) and as a result, high levels 
of sirolimus are not achieved (<100 ng/mL) (Danesi, 2013). Clinically, administration of ABI-009 
at 56 mg/m2 IV weekly led to a much higher exposure to sirolimus (sirolimus) as compared with 
daily oral sirolimus at 5 mg/day (Cmax 116-186 fold, AUC 9-16 fold, AUC/dose ~3-5 fold higher with 
ABI-009), temsirolimus weekly IV at 25 mg/week (Cmax 44 fold, AUC 7 fold, AUC/dose 2 fold for 
ABI-009), and daily oral everolimus at 4-10 mg/day (Cmax 47-65 fold, AUC 7-17 fold, AUC/dose ~5 
fold higher with ABI-009) (Garrido-Laguna, 2010; Danesi, 2013; Gonzalez-Angulo, 2013). Unlike 
with other mTOR inhibitors, micromolar concentrations are reached and maintained for several 
hours with ABI-009 which could potentially circumvent acquired resistance to mTOR inhibitors 
via retroactivation of AKT by TORC2 (Banaszynski, 2005; Shor, 2008). The high exposure achieved 
with ABI-009 with acceptable safety profile could be highly relevant to the treatment of 
aggressive cancers. 
As an albumin-bound nanoparticle, ABI-009 is potentially a suitable treatment option for disease 
indications in the brain, including epilepsy. In a biodistribution study in rats, radiolabeled ABI-009 
showed significant brain uptake at 5 days (Aadi internal data). As shown in Figure 1, the 
radioactivity accumulation in the brain was comparable to all other major organs 5 days after a 
single IV dose of radiolabeled ABI-009. 


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Figure 1: 
Distribution of Radioactivity in Tissues in Male Rats 
 
Further, in a recent PK/biodistribution study, female SD rats received a single IV dose of ABI-009 
at 1.7, 9.5, and 17 mg/kg. The doses of 9.5 and 17 mg/kg corresponded with 56 and 100 mg/m2 
human doses, respectively. The sirolimus concentrations in blood and major organs at different 
time points between 2 to 120 hours were analyzed by LC-MS/MS. In the blood and well-perfused 
organs, there was a high initial peak of sirolimus concentration that dropped quickly with time 
between 2 hours and 24 hours. In contrast, sirolimus concentrations in the brain were relatively 
low at 2 hours but maintained at a steady level over time. After 5 days, sirolimus level in the brain 
was similar or higher compared with other organs, suggesting a preferential accumulation even 
when the blood levels were low (Figure 2). At all times and all doses, tissue levels of sirolimus in 
the brain were well above the threshold of 5-20 ng/mL (or ng/g) which is required for therapeutic 
activity. The brain was also the only tissue that showed a dose response for tissue levels after at 
120 hours (5 days) after administration, suggesting that high ABI-009 doses may be desirable to 
achieve improved clinical benefits for the treatment of disease conditions in the brain. The 
tissue/blood ratios for all tissues except the brain remained fairly constant over 120 hours. In 
contrast, the brain/blood ratio increased over the same time period (Figure 3). In summary, 
results from this study clearly demonstrated substantial and prolonged drug distribution to the 
brain with ABI-009 IV administration. 
 




ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
35 
MRZ crosses the blood brain barrier, combination treatment with ABI-009 and MRZ may provide 
benefit to patients with high grade gliomas.  
The overall safety profile of MRZ shows limited overlapping toxicities with ABI-009, which mainly 
include general non-hematological toxicities (constipation, diarrhea, nausea, vomiting, and 
fatigue). 
1.5.3. 
Rationale for Combination of ABI-009 plus Lomustine (CCNU) 
Previous studies have shown that mTOR inhibition can sensitize cancer cells to alkylating 
chemotherapy (Tanaka, 2007; Cejka, 2008). In a study by Tanaka et al., sirolimus enhanced 
cytotoxicity induced by alkylating agent ACNU in human U251 malignant glioma cells (Tanaka, 
2007), suggesting that the combination of ABI-009 and lomustine (CCNU) may provide improved 
anticancer activity. 
1.5.4. 
Rationale for Combination of ABI-009 plus Temozolomide (± Radiotherapy) 
Temozolomide is a standard treatment for ndGBM. In a recent in vitro study, the combination of 
the mTOR inhibitor temsirolimus with TMZ significantly increased growth inhibition and 
apoptosis in melanoma cells compared with either agent alone (Niessner, 2017). The improved 
antitumor activity is mediated by the downregulation of the anti-apoptotic protein Mcl-1 and the 
upregulation of the Wnt antagonist Dickkopf homologue 1 (DKK1). In a phase 1 study in patients 
with ndGBM (RTOG 0913), daily oral everolimus (10 mg) combined with both concurrent 
radiation and TMZ and adjuvant TMZ, was relatively well tolerated with an acceptable toxicity 
profile (Chinnaiyan, 2013). In a phase 2 study in patients with ndGBM (N057K), the combination 
of everolimus with conventional TMZ-based chemoradiotherapy resulted in OS rate at 12 months 
of 64%, median OS of 15.8 months, and median time to progression of 6.4 months (Ma, 2015). 
The combination had moderate toxicity but did not show an appreciable survival benefit 
compared with historical controls with conventional therapy. Based on preclinical and clinical 
study results, the novel mTOR inhibitor ABI-009 may potentially improve the activity of TMZ in 
ndGBM and rGBM settings. 
Further, mTOR inhibitors have been shown to enhance the effects of radiation therapy. In a 
preclinical study with MCF7 breast cancer cells, sirolimus treatment led to significant suppression 
of homologous recombination (HR) and nonhomologous end joining (NHEJ), 2 major mechanisms 
required for repairing ionizing radiation-induced double-strand DNA break (Chen, 2011). In 
androgen receptor-positive prostate cancer cells, sirolimus and temsirolimus showed strong 
radiosensitization effects when used in combination with radiation (Schiewer, 2012). Increased 
phospho-mTOR and phospho-S6 proteins were also detected in irradiated human umbilical vein 
endothelial cells (HUVEC). The combination of everolimus and radiation resulted in a significant 
reduction in vasculature and blood flow in glioma xenografts in mice compared with mice treated 
with everolimus or radiation alone (Shinohara, 2005). Taken together, these study results support 
the induction treatment with ABI-009 prior to chemoradiation therapy, the approach used in Arm 
B of this study for the treatment of patients with ndGBM.  


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
36 
1.5.5. 
Justification for ABI-009 Dose Selections 
In Arm A (recurrent high-grade glioma), Cohort 1, single agent ABI-009 will be administered IV 
as a 30-minute infusion at a dose of 100 mg/m2 on Days 1 and 8 of every 21-day cycle, as 100 
mg/m2 was determined to be the MTD in a previous phase 1 study in patients with solid tumors 
(Gonzalez-Angulo, 2013).  
In Arm A, Cohort 2-5, the combination cohorts, ABI-009 will be administered IV at 60 mg/m2. At 
the discretion of the investigator, if ABI-009 is well tolerated (no DLTs, dose modifications, or 
dose delays) at 60 mg/m2 in the first 3 patients in the cohort, the dose may be increased to 75 
mg/m2 for subsequent patients in the cohort. This dose is 40% lower than the MTD of 100 mg/m2 
potentially reducing the risk of overlapping toxicities with the combination drugs. The 
administration of ABI-009 at 56 mg/m2 resulted in significantly higher exposure to sirolimus 
compared with weekly IV temsirolimus at 25 mg/week (Cmax 44 fold higher, AUC 7 fold, AUC/dose 
2 fold higher for ABI-009) and daily oral everolimus at 4-10 mg/day (Cmax 47-65 fold higher, AUC 
7-17 fold, AUC/dose ~5 fold higher for ABI-009) (Danesi, 2013; Gonzalez-Angulo, 2013). 
For patients with recurrent disease, ABI-009 will be administered on Days 1, 8 and 15, of a 28-
day cycle when combined with TMZ, or BEV, or MRZ, or on Days 1 and 8 of a 21-day cycle when 
combined with CCNU to align with established dosing regimens of the combination agents. It is 
hypothesized that lower doses of BEV may potentially improve chemotherapy delivery and 
ultimately patient outcome (Weathers, 2016). In a retrospective analysis, low dose intensity BEV 
(<5 mg/kg/week) was associated with improved PFS and OS with an inverse relationship seen 
between dose-intensity and OS when compared with normal dose intensity BEV at 10 mg/kg 
(Lorgis, 2012). Therefore, the BEV dose of 5 mg/kg is chosen for this study. Due to potential 
hematologic toxicities of ABI-009 and myelosuppression common with CCNU, the CCNU dose to 
be administered on Day 1 of each odd cycle will start at 90 mg/m2 with a maximum dose of 160 
mg per cycle (approximately 70% of the 130 mg/m2 starting dose in patients with brain tumors) 
and will be discontinued for compromised bone marrow function. 
In Arm B (ndGBM), single agent ABI-009 will be administered IV at 60 mg/m2 once weekly for 4 
weeks during induction treatment prior to standard RT + TMZ with the intent of eliminating any 
residual disease following surgery. ABI-009 will be administered IV at 60 mg/m2 on Days 8 and 15 
of a 21-day cycle, for 2 cycles, during concomitant RT + TMZ to provide a rest period before 
continuing with ABI-009 treatment. ABI-009 will then be administered IV at 60 mg/m2 on Days 1, 
8, and 15 of a 28-day cycle with adjuvant TMZ. This dose is 40% lower than the MTD of 100 mg/m2 
potentially reducing the risk of overlapping toxicities with the combination therapy. 
The use of induction period will allow us to evaluate single agent activity in newly diagnosed GBM 
and is a well-established approach. Several clinical trials have demonstrated the feasibility and 
safety of administering 1 to 4 cycles of chemotherapy prior to radiation therapy in patients with 
malignant gliomas (Recht, 1990; Watne, 1992; Gilbert, 2002; Chang, 2004), and that the delay to 
radiation does not appear to compromise patient outcome (Kirby, 1996; Fetell, 1997; Vinolas, 
2002; Wick, 2002; Diaz, 2005). Much of the early work focused on chemotherapies in wide use 
at the time: alkylating agents such as BCNU, procarbazine, CCNU, and TMZ; platinums such as 
cisplatin and carboplatin, and other alkaloids such as vincristine, etoposide, and irinotecan. Some 
of the studies reported tumor response to chemotherapy prior to initiation of radiation therapy, 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
37 
while others reported tumor response to the sequence of both chemotherapy and radiation 
therapy. A few studies demonstrated early evidence that agents were clearly inactive (Fetell, 
1997; Hochberg, 2000; Balana, 2014). 
1.5.6. 
Rationale for Performing the Study 
Patients with HGG represent a population with a large unmet medical need. Based on the 
significance of mTOR pathway in GBM pathology, this study will evaluate the efficacy and safety 
of ABI-009 as a single agent and in combination with other therapeutic agents for the treatment 
of recurrent HGG. The best regimen among the combination arms may be further tested in 
additional clinical studies. This study will also evaluate the efficacy and safety of the addition of 
ABI-009 to the standard of care treatment for patients with ndGBM. 
 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
38 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives  
Arm A: Recurrent High-grade Glioma 
Primary Objective 
1. To evaluate the efficacy of IV ABI-009 as a single agent and as a combination of ABI-009 + 
TMZ, ABI-009 + BEV, ABI-009 + CCNU, and ABI-009 + MRZ in patients with recurrent HGG. 
Secondary Objective 
1. To evaluate the safety of ABI-009 as a single agent and in combination with TMZ, BEV, or 
CCNU, or MRZ in patients with recurrent HGG. 
 
Arm B: Newly-diagnosed Glioblastoma 
Primary Objectives 
1. To evaluate the efficacy of the combination of ABI-009 and standard TMZ-based 
chemoradiotherapy. 
Secondary Objectives 
1. To evaluate the safety and efficacy of ABI-009 (Induction Treatment).  
2. To evaluate the safety of the combination of ABI-009 + TMZ + RT (Concomitant Treatment).  
3. To evaluate the safety of the combination of ABI-009 + TMZ (Adjuvant Treatment). 
 
Exploratory Objective for Arms A and B 
1. To evaluate tumor biomarkers related to mTOR pathway using pre-study archived tissue 
samples and if available, post-treatment tumor tissue samples. 
2. To evaluate blood biomarkers and correlate to outcomes. 
2.2. 
Endpoints 
Primary Endpoint for Arms A and B  
Objective ORR, according to RANO 2010 criteria 
Secondary Endpoints for Arms A and B 
PFS rate at 6 months, PFS rate at 12 months, median PFS, OS at 12 months, median OS, and AEs 
Exploratory Endpoints for Arms A and B 
• Assessment of pre-treatment archived tumor samples for the activity of mTOR pathway and 
correlation with activity/tolerability 
• If available, tumor biomarkers post-progression 
• To evaluate blood biomarkers and correlate to outcomes 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
39 
3. 
OVERALL STUDY DESIGN 
3.1. 
Study Design 
This is a prospective, multi-cohort, non-randomized, open-label phase 2 study. Arm A (recurrent 
high-grade glioma) of the study will have 5 treatment cohorts, aiming to determine the efficacy 
and safety profile of ABI-009 as a single agent and in combination with TMZ, BEV, CCNU, and MRZ 
in patients with recurrent HGG, who have not previously received any mTOR inhibitors. Arm A of 
the study will use Simon’s two-stage design. Up to 19 patients per cohort will be enrolled: initially 
9 patients will be enrolled with a stopping rule that only if there are 2 or more positive responses 
will the study proceed to further enrollment of the next 10 patients. Patients will continue 
therapy until disease progression, unacceptable toxicity, until in the opinion of the investigator 
the patient is no longer benefiting from therapy, or at the discretion of the patient. 
In Cohort 1 of Arm A, ABI-009 will be administered IV as a 30-minute infusion at 100 mg/m2 on 
Days 1 and 8 of every 21-day cycle. Two dose reduction levels will be allowed: 75 mg/m2 and 60 
mg/m2. 
In Cohort 2 of Arm A, ABI-009 60 mg/m2 is administered on Days 1, 8, and 15 of every 28-day 
cycle with oral TMZ 50 mg/m2 daily.  
In Cohort 3 of Arm A, ABI-009 60 mg/m2 is administered on Days 1, 8, and 15 of every 28-day 
cycle with BEV 5 mg/m2 on Days 1 and 15. Bevacizumab will be administered as an IV infusion (90 
minutes 1st dose, 60 minutes 2nd dose, and 30 minutes afterward assuming tolerability). 
In Cohort 4 of Arm A, ABI-009 60 mg/m2 is administered on Days 1 and 8 of every 21-day cycle 
with oral CCNU 90 mg/m2 on Day 1 of each odd cycle (ie, every 6 weeks).  
In Cohort 5 of Arm A, ABI-009 60 mg/m2 is administered on Days 1, 8, and 15 of every 28-day 
cycle with MRZ administered IV as a 10-minute infusion at 0.8 mg/m2 on Days 1, 8, and 15 of 
every 28-day cycle. 
For the combination cohorts, 2 dose reduction levels will be allowed for ABI-009: 45 mg/m2 and 
30 mg/m2. At the discretion of the investigator, if ABI-009 is well tolerated (no DLTs, dose 
modifications, or dose delays) at 60 mg/m2 in the first 3 patients in the cohort, the dose may be 
increased to 75 mg/m2 for subsequent patients in the cohort. Intrapatient dose escalation is not 
allowed.  
 
Arm B (ndGBM) of the study will examine the effect of the addition of ABI-009 to the standard of 
care treatment of TMZ+RT (Concomitant Treatment) and TMZ (Adjuvant Treatment) in patients 
with ndGBM who can have either non-measurable disease or enhancing tumors after surgery and 
have not previously received any local or systemic therapy.  Up to 19 patients will be enrolled in 
Arm B. 
Induction Treatment: ABI-009 
Induction Treatment will start at least 3-8 weeks following surgical resection of ndGBM and after 
the surgical wound is fully healed.  


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
40 
• ABI-009 will be administered IV at 60 mg/m2 as a 30-minute IV infusion every week for 4 
weeks. Three dose reduction levels will be allowed: 45, 30, and 20 mg/m2. 
Concomitant Treatment: ABI-009 + TMZ + RT 
Concomitant Treatment will start 1 week after the completion of Induction Treatment and will 
last for 6 weeks.  
• ABI-009 will be administered IV at 60 mg/m2 as a 30-minute IV infusion on Days 8 and 15 
of every 21-day cycle. Three dose reduction levels will be allowed: 45, 30, and 20 mg/m2. 
• TMZ will be administered at 75 mg/m2 PO daily for 6 weeks as part of routine therapy for 
GBM.  
• Focal RT will be given daily at 30x 200 cGy, 5 days/week for a total dose of 60 Gy (or 
equivalent regimens as per RTOG guidelines) as part of routine therapy for GBM. 
Adjuvant Treatment: ABI-009 + TMZ 
Adjuvant Treatment will start 4 weeks after the completion of Concomitant Treatment (any time 
during the 4th week) and will last for 24 weeks.  
• ABI-009 will be administered IV at 60 mg/m2 as a 30-minute IV infusion on Days 1, 8, and 
15 of every 28-day cycle for 6 cycles. Three dose reduction levels will be allowed: 45, 30, 
and 20 mg/m2. 
• TMZ will be administered at 150 mg/m2 PO daily on Days 1-5 of every 28-day cycle for 6 
cycles. In the absence of toxicity, TMZ may be administered at 200 mg/m2/day starting in 
Cycle 2. 
3.2. 
Study Duration, End of Study, End of Treatment, End of Treatment Visit, Follow-up 
Period 
The Arm A of this study is expected to take approximately 32 months from first patient enrolled 
to last patient follow-up, including approximately 24 months of enrollment period, an estimated 
6 months of treatment (or until unacceptable toxicity or disease progression) and an end of 
treatment visit within 4 weeks after last treatment. 
The Arm B of this study is expected to take approximately 24 months from first patient enrolled 
to last patient follow-up, including approximately 16 months of enrollment period, up to 12 
months of treatment (or until unacceptable toxicity or disease progression) and an end of 
treatment visit within 4 weeks after last treatment. 
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 4 weeks 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 is the on-study time period after the EOT Visit. All patients that discontinue 
study drug and have not withdrawn full consent to participate in the study will continue in the 
follow-up phase for survival and initiation anticancer therapy. Follow up will continue 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
41 
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  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
42 
4. 
STUDY POPULATION 
4.1. 
Study Population 
The study population include patients with progressive HGG following prior therapy, who have 
not been previously treated with mTOR inhibitors; or patients with ndGBM who can have either 
non-measurable disease or enhancing tumors after surgery. Use of the Optune device is not 
allowed in Stage 1 of the study.  Usage of Optune may be considered in Stage 2 of the study after 
review of the safety data. 
Arm A (recurrent high-grade glioma): Patients at least 18 years of age with histologic evidence 
of high grade glioma and radiographic evidence of recurrence or disease progression (defined as 
either a greater than 25% increase in the largest bi-dimensional product of enhancement, a new 
enhancing lesion, or a significant increase in T2 FLAIR) following prior therapy. Patients must have 
previously failed a treatment regimen, including radiation and/or chemotherapy.   
Arm B (ndGBM): Patients at least 18 years of age with histologic evidence of ndGBM. Patients 
must have surgery and can have either non-measurable disease or enhancing tumors after 
surgery detected by MRI, and have not previously received any local or systemic therapy for their 
GBM. 
4.2. 
Number of Patients 
Arm A: up to 95 response-evaluable patients will be enrolled (up to 19 per cohort; 5 cohorts).  
Arm B: up to 19 response-evaluable patients will be enrolled. 
4.3. 
Inclusion Criteria  
Inclusion Criteria Common for Both Arms A and B 
A patient will be eligible for inclusion in this study only if all of the following criteria are met: 
1. Understand and voluntarily sign and date an informed consent document prior to any study 
specific assessments/procedures. 
2. Males and females of age ≥18 years at the time of signing the informed consent document. 
3. Karnofsky Performance Status (KPS) score ≥70%. 
4. No investigational agent within 4 weeks prior to the first dose of study drug. 
5. All AEs resulting from prior therapy and surgery must have resolved to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 grade ≤1 (except 
for laboratory parameters outlined below). 
6. Adequate hematological, renal, and hepatic function (assessment performed within 14 days 
prior to study treatment): 
- Absolute neutrophil count (ANC) ≥1.5 x 109/L 
- Platelets ≥100 x 109/L 
- Hemoglobin ≥9 g/dL.  
- Serum creatinine ≤1.5 x upper limit of laboratory normal (ULN); Total serum 
bilirubin ≤1.5 x ULN, or ≤ 3 x ULN if Gilbert’s disease is documented 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
43 
− Aspartate Serine Transaminase (AST), Aspartate Leucine Transaminase (ALT), Alkaline 
Phosphatase (ALP) ≤2.5 x ULN 
− Serum triglyceride <300 mg/dL; serum cholesterol <350 mg/dL 
7. Patients must be without seizures for at least 14 days prior to enrollment, and patients who 
receive treatment with anti-epileptic drugs (AEDs) must be on stable doses for at least 14 
days prior to enrollment. Patients must be off EIAEDs for at least 14 days prior to enrollment 
and cannot be on EIAEDs at any time during the study. 
8. Steroid therapy for control of cerebral edema is allowed at the discretion of the Investigator. 
Patients should be on stable or decreasing dose of corticosteroids for at least 1 week prior to 
the first dose of study drug.  
9. 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.  
• 
Male patients with partners of child-bearing potential must agree to take 
contraceptive measures for the duration of treatment and for 3 months after the last 
study treatment. 
10. Willing and able to adhere to the study visit schedule and other protocol requirements. 
 
Inclusion Criteria Specific for Arm A 
1. All patients must have histologic evidence of high grade glioma (WHO grade 3 or grade 4) and 
radiographic evidence of recurrence or disease progression (defined as either a greater than 
25% increase in the largest bi-dimensional product of enhancement, a new enhancing lesion, 
or a significant increase in T2 FLAIR). Patients must have at least 1 measurable lesion by RANO 
criteria (≥10 mm in 2 perpendicular diameters). 
2. Patients must have previously failed a treatment regimen, including radiation and/or 
chemotherapy. 
3. No prior treatment with mTOR inhibitors.  
4. No prior treatment with TMZ for the treatment of recurrent glioma for patients entering the 
ABI-009 + TMZ cohort. 
5. No prior treatment with BEV or any other anti-angiogenic agents, including sorafenib, 
sunitinib, axitinib, pazopanib, or cilengitide for the ABI-009 + BEV arm. 
6. No prior treatment with CCNU for the ABI-009 + CCNU arm. 
7. No prior treatment with MRZ or any other proteasome inhibitors, including bortezomib (BTZ), 
carfilzomib (CFZ), or ixazomib (IXZ), for patients entering the ABI-009 + MRZ cohort. 
8. At least 4 weeks from surgical resection and at least 12 weeks from the end of radiotherapy 
prior to enrollment in this study, unless relapse is confirmed by tumor biopsy or new lesion 
outside of radiation field, or if there are two MRIs confirming progressive disease (PD) that 
are approximately 4 weeks apart. 
 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
44 
Inclusion Criteria Specific for Arm B 
1. Histologically confirmed ndGBM. 
2. Patients must have had surgery and can have either non-measurable disease or a measurable 
post-contrast lesion after surgery detected by MRI. 
3. No prior treatment with mTOR inhibitors, and no prior local or systemic therapy for GBM. 
4.4. 
Exclusion Criteria  
Exclusion Criteria Common for Both Arms A and B 
A patient will not be eligible for inclusion in this study if any of the following criteria apply: 
1. Co-medication or concomitant therapy that may interfere with study results, including anti-
coagulants and enzyme-Inducing anti-epileptic drugs (EIAEDs).   
2. History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months. 
3. Pregnant or breast feeding. 
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
requiring IV antibiotics & psychiatric illness/social situations that would limit compliance with 
study requirements, or disorders associated with significant immunocompromised state. 
5. Active gastrointestinal bleeding. 
6. Uncontrolled hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood 
pressure ≥90 mm Hg. 
7. Patients with history of intestinal perforations, fistula, hemorrhages and/or hemoptysis ≤6 
months prior to first study treatment. 
8. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. 
9. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary 
hypertension.  
10. Use of strong inhibitors and inducers of CYP3A4 (such as EIAEDs including carbamazepine, 
phenytoin, oxcarbazepine, topiramate, among others) 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.  
11. Known other previous/current malignancy requiring treatment within ≤ 3 years except for 
limited disease treated with curative intent, such as in situ prostate cancer, intracapsular 
renal cancer, cervical carcinoma in situ, squamous or basal cell skin carcinoma, and superficial 
bladder carcinoma.  
12. Any comorbid condition that restricts the use of study drug and confounds the ability to 
interpret data from the study as judged by the Investigator or Medical Monitor.  
13. Known infection with human Immunodeficiency Virus (HIV), or active Hepatitis B or Hepatitis 
C. 
 
 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
45 
5. 
TABLE OF EVENTS 
All study assessments, including safety and response assessments, are described in Table 1, 
Table 2, and Table 3, and summarized by type of study visit in the following pages.  All visit dates 
and procedures are relative to Day 1, defined as the first day of treatment administration, of each 
cycle. 
 
 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432 
 
 
Confidential and Proprietary 
46 
Table 1: 
Schedule of Assessments for Arm A 21-day Cycles (Cohorts 1 and 4) 
Assessment  
Screening * 
 
Cycle 1  
Cycle 2 through Last Cycle 
End of Treatment (EOT) 
Visit j 
Follow-up 
Period k 
Day 1 * 
Day 8 
Day 1  
Day 8 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
X 
 
X 
 
Vital Signs, Weight, and Height a 
X 
X 
X 
X 
X 
X 
 
BSA Calculation b 
 
X 
 
 
 
 
 
Prior/Concomitant Medication Evaluation c 
X 
X 
X 
X 
X 
X 
 
Prior/Concurrent Procedures Evaluation c 
X 
X 
X 
X 
X 
X 
 
KPS 
X 
X 
 
X 
 
X 
 
Pregnancy Test d 
X 
 
 
 
 
X 
 
Tumor Sample for Biomarkers e 
X 
 
 
 
X 
Adverse Events  
 
Continuous starting from signing of Informed Consent until 28 days after last dose of IP 
ABI-009 Dosing (Cohorts 1 and 4) f 
 
X 
X 
X 
X 
 
 
CCNU Dosing (Cohort 4) 
 
X 
 
Odd cycles  
 
 
 
Survival Status  
 
 
 
 
 
 
X 
Local Laboratory Assessments 
Clinical Chemistry Panel 
X 
X 
 
X 
 
X 
 
CBC/Differential 
X 
X 
X 
X 
X 
X 
 
PT, PTT, INR 
X 
 
 
 
 
 
 
HIV, HBV sAg, HBV cAb, HCV Ab 
X 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
Fasting Lipids g 
X 
 
 
X  
 
 
 
Sirolimus level h 
 
X 
X 
X 
X 
 
 
Blood collection for research  
 
X 
 
X 
 
X 
 
Imaging and Efficacy Assessments 
MRI i 
X 
 
 
Every 6 weeks (±7 days) 
after C1 D1 
X 
 
Unless otherwise specified, visits must occur within ±3 days of the planned visit date. 
* Screening evaluations to be obtained ≤21 days prior to study treatment Day 1 unless specified otherwise. Day 1 evaluations can be omitted if screening evaluations are 
performed within 72 hours of Cycle 1 Day 1. 
a. 
Height is only collected at baseline.  
b. 
BSA calculated ONLY on C1/D1; to be recalculated only if the weight changes by >10% in subsequent cycles. 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432 
 
 
Confidential and Proprietary 
47 
c. 
Prior: record all medications taken and procedures done ≤28 days prior to screening; Concomitant: any medications or procedures after the signing of informed consent. 
At the end of treatment visit, information on concomitant medications or procedures will be collected until 28 days after the last dose of IP. 
d. 
For females of childbearing potential only.  A serum β-hCG pregnancy test must be performed to assess patient eligibility at screening prior to first IP administration 
(negative results required for IP administration).  Urine pregnancy test will be performed at EOT Visit (can be done locally) and as clinically indicated as per institutional 
guidelines. 
e. 
It is mandatory for patients to provide surgical samples, if they are available and local regulations allow it. Ensure the surgical pathology report is submitted with tumor 
tissue sample. Archival or fresh tumor sample: formalin-fixed, paraffin-embedded (FFPE) tumor tissue (preferred) or unstained slides (20-30 slides) from biopsy will be 
collected (refer to Instruction Sheet for details). On-study tumor tissue collection, if available, is optional only for patients who provide additional consent, and will be 
collected upon disease progression and/or end of last dose of IP. 
f. 
ABI-009 must be administered after all study specific assessments are done in a visit. 
g. 
Fasting lipids at base line and Day 1 of every even number cycle starting with Cycle 2 (eg, C2, C4, C6, etc.). 
h. 
On Cycle 1 Day 1, sirolimus levels are done immediately prior to the end of infusion (ie, at 30 mins post start of infusion) and analyzed by a central lab. Thereafter on 
subsequent treatment days in Cycles 1 and 2, only trough levels (predose) of sirolimus are done by local labs.  
i. 
Screening MRI scans must be performed within 21 days prior to study day 1, preferably as close to the day of enrollment as possible. Tumor evaluation by MRI will be 
performed during screening; every 6 weeks (±7 days) until disease progression. EOT visit MRI should be performed only for those patients that discontinue treatment 
for a reason other than disease progression. If an initial observation of objective ORR (confirmed response [CR] or PR) is made, a confirmation scan should be done at 6 
weeks after initial observation.  
j. 
End of Treatment Visit must occur within 4 weeks after the last dose of ABI-009. 
k. 
Follow-up for survival and initiation of anticancer therapy can be performed by telephone contact every 12 weeks (±3 weeks) or more frequently if needed, from EOT 
Visit. All patients that discontinue study drug and have not withdrawn full consent to participate in the study will continue in the follow-up phase for survival and 
anticancer therapy. This evaluation may be made by record review and/or telephone contact. 
 
 
 
 


ABI-009  
 
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Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
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Table 2: 
Schedule of Assessments for Arm A 28-day Cycles (Cohorts 2, 3, and 5) 
Assessment  
Screening 
* 
Cycle 1  
Cycle 2 through Last Cycle 
End of 
Treatment 
(EOT) Visit k 
Follow-
up 
Period l 
Day 1* 
Day 8 
Day 15 
Day 1 
Day 8 
Day 15 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
X 
 
 
X 
 
Vital Signs, Weight and Height a 
X 
X 
X 
X 
X 
X 
X 
X 
 
BSA Calculation b 
 
X 
 
 
 
 
 
 
 
Prior/Concomitant Medication Evaluation c 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/Concurrent Procedures Evaluation c 
X 
X 
X 
X 
X 
X 
X 
X 
 
KPS 
X 
X 
 
 
X 
 
 
X 
 
Pregnancy Test d 
X 
 
 
 
 
 
 
X 
 
Tumor Sample for Biomarkers e 
X 
 
 
 
 
 
 
X 
Adverse Events  
 
Continuous starting from signing of Informed Consent until 28 days after last dose of IP 
ABI-009 Dosing (Cohort 2, 3 and 5) f 
 
X 
X 
X 
X 
X 
X 
 
 
TMZ Dosing (Cohort 2) 
 
Daily 
Daily 
 
 
BEV Dosing (Cohort 3) f 
 
X 
 
X 
X 
 
X 
 
 
MRZ Dosing (Cohort 5) 
 
X 
X 
X 
X 
X 
X 
 
 
Survival Status  
 
 
 
 
 
 
 
 
X 
Local Laboratory Assessments 
Clinical Chemistry Panel 
X 
X 
 
 
X 
 
 
X 
 
CBC/Differential 
X 
X 
X 
X 
X 
X 
X 
X 
 
PT, PTT, INR 
X 
 
 
 
 
 
 
 
 
HIV, HBV sAg, HBV cAb, HCV Ab 
X 
 
 
 
 
 
 
 
 
Urinalysis g 
X 
X 
 
X 
X 
 
X 
 
 
Fasting Lipids h 
X 
 
 
 
X  
 
 
 
 
Sirolimus level i 
 
X 
X 
X 
X 
X 
X 
 
 
Blood collection for research  
 
X 
 
 
X 
 
 
X 
 
Imaging and Efficacy Assessments 
MRI j 
X 
Every 8 weeks (±7 days) after C1 D1  
X 
 
Unless otherwise specified, visits must occur within ±3 days of the planned visit date. 
* Screening evaluations to be obtained ≤21 days prior to study treatment Day 1 unless specified otherwise. Day 1 evaluations can be omitted if screening evaluations are 
performed within 72 hours of Cycle 1 Day 1. 


ABI-009  
 
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Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432 
 
 
Confidential and Proprietary 
49 
a. 
Height is only collected at baseline. 
b. 
BSA calculated ONLY on C1D1; to be recalculated only if the weight changes by >10% in subsequent cycles. 
c. 
Prior: record all medications taken and procedures done ≤ 28 days prior to screening; Concomitant: any medications or procedures after the signing of informed consent.  
At the end of treatment visit, information on concomitant medications or procedures will be collected until 28 days after the last dose of IP. 
d. 
For females of childbearing potential only. A serum β-hCG pregnancy test must be performed to assess patient eligibility at screening prior to first IP administration 
(negative results required for IP administration).  Urine pregnancy test will be performed at EOT Visit (can be done locally) and as clinically indicated as per institutional 
guidelines. 
e. 
It is mandatory for patients to provide surgical samples, if they are available and local regulations allow it. Ensure the surgical pathology report is submitted with tumor 
tissue sample. Archival or fresh tumor sample: formalin-fixed, paraffin-embedded (FFPE) tumor tissue (preferred) or unstained slides (20-30 slides) from biopsy will be 
collected (refer to Instruction Sheet for details). On-study tumor tissue collection, if available, is optional only for patients who provide additional consent, and will be 
collected upon disease progression and/or end of last dose of IP. 
f. 
ABI-009 and Bev must be administered after all study specific assessments are done in a visit. 
g. 
For Cohort 2 ABI-009 + TMZ and Cohort 5 ABI-009 + MRZ, urinalysis is done at screening only. For Cohort 3 ABI-009 + BEV, urinalysis is done at screening and with BEV 
treatment every 2 weeks. Monitor proteinuria by dipstick urine analysis with serial urinalyses during BEV therapy. Patients with a 2+ or greater urine dipstick reading 
should undergo further assessment with a 24-hour urine collection. Suspend BEV for >2 grams of proteinuria/24 hours and resume when proteinuria is <2gm/24 hours. 
Discontinue BEV in patients with nephrotic syndrome. 
h. 
Fasting lipids at base line and Day 1 of every even number cycle starting with Cycle 2 (eg, C2, C4, C6, etc.). 
i. 
On Cycle 1 Day 1, sirolimus levels are done immediately prior to the end of infusion (ie, at 30 mins post start of infusion) and analyzed by a central lab. Thereafter on 
subsequent treatment days in Cycles 1 and 2, only trough levels (predose) of sirolimus are done by local labs.  
j. 
Screening MRI scans must be performed within 21 days prior to study day 1, preferably as close to the day of enrollment as possible. Tumor evaluation by MRI will be 
performed during screening and every 8 weeks (±7 days) until disease progression. EOT visit MRI should be performed only for those patients that discontinue treatment 
for a reason other than disease progression. If an initial observation of objective ORR (CR or PR) is made, a confirmation scan should be done at 8 weeks after initial 
observation.  
k. 
End of Treatment Visit must occur within 4 weeks after the last dose of ABI-009. 
l. 
Follow-up for survival and initiation of anticancer therapy can be performed by telephone contact every 12 weeks (±3 weeks) or more frequently if needed, from EOT 
Visit. All patients that discontinue study drug and have not withdrawn full consent to participate in the study will continue in the follow-up phase for survival and anticancer 
therapy. This evaluation may be made by record review and/or telephone contact. 
 
 
 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432 
 
 
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50 
Table 3: 
Schedule of Assessments for Arm B 
Assessment 
Screening * 
 
Induction Treatment j 
Concomitant  
Treatment j 
Adjuvant 
Treatment j 
End of 
Treatment 
(EOT) Visit k 
Follow-
up 
Period l 
D1 * 
D8 
D15 
D21 
D1 
D8 
D15 
D1 
D8 
D15 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Vital Signs, Weight, and Height a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BSA Calculation b 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Medication Evaluation c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/Concurrent Procedures Evaluation c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
KPS 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Pregnancy Test d 
X 
 
 
 
X 
 
Survival status  
 
 
 
 
 
X 
Tumor Sample for Biomarkers e 
X 
 
X 
Adverse Events  
 
Continuous starting from signing of Informed Consent until 28 days after last dose of IP 
ABI-009 Dosing f 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
TMZ Dosing 
 
 
Daily for 6 weeks 
Daily, Day 1-5 of 
28-day cycle 
 
 
Radiotherapy 
 
 
Daily (M-F) for 30 days 
 
 
 
Local Laboratory Assessments 
Clinical Chemistry Panel 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
CBC/Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PT, PTT, INR 
X 
 
 
 
 
 
HIV, HBV sAg, HBV cAb, HCV Ab 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
Fasting Lipids g 
X 
 
 
 
 
X  
 
 
X  
 
 
 
 
Sirolimus level h 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Blood collection for research 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Imaging and Efficacy Assessments 
MRI i 
X 
 
D1 
Prior to the start 
of and every 8 
weeks during 
X 
 
Unless otherwise specified, visits must occur within ± 3 days of the planned visit date. 


ABI-009  
 
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Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
 
IND 138432 
 
 
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* Screening evaluations to be obtained ≤21 days prior to study treatment Day 1 unless specified otherwise. Day 1 evaluations can be omitted if screening evaluations are 
performed within 72 hours of Cycle 1 Day 1. 
a. 
Height is only collected at baseline.  
b. 
BSA calculated ONLY on C1/D1; to be recalculated only if the weight changes by > 10% in subsequent cycles. 
c. 
Prior: record all medications taken and procedures done ≤ 28 days prior to screening; Concomitant: any medications or procedures after the signing of informed consent.  At 
the end of treatment visit, information on concomitant medications or procedures will be collected until 28 days after the last dose of IP. 
d. 
For females of childbearing potential only. A serum β-hCG pregnancy test must be performed to assess patient eligibility at screening prior to first IP administration 
(negative results required for IP administration).  Urine pregnancy test will be performed at EOT Visit (can be done locally) and as clinically indicated as per institutional 
guidelines. 
e. 
It is mandatory for patients to provide surgical samples, if they are available and local regulations allow it. Ensure the surgical pathology report is submitted with tumor 
tissue sample. Archival or fresh tumor sample: formalin-fixed, paraffin-embedded (FFPE) tumor tissue (preferred) or unstained slides (20-30 slides) from biopsy will be 
collected (refer to Instruction Sheet for details). On-study tumor tissue collection, if available, is optional only for patients who provide additional consent, and will be 
collected upon disease progression and/or end of last dose of IP. 
f. 
ABI-009 dosing schedule: Induction Treatment: weekly for 4 weeks; Concomitant Treatment: 2 weeks out of 21-day cycle; Adjuvant Treatment: 3 weeks out of every 28-
day cycle. ABI-009 must be administered after all study specific assessments are done in a visit. Adjuvant Treatment will start 4 weeks (any time during the 4th week) 
after the completion of Concomitant Treatment and will last for 24 weeks. 
g. 
Fasting lipids at base line, Day 1 of the 1st cycle in Concomitant Treatment, and Day 1 of every odd numbered cycle in Adjuvant Treatment (C1, C3, and C5).  
h. 
On Day 1 of the Induction Treatment, sirolimus levels are done immediately prior to the end of infusion (ie, at 30 mins post start of infusion) and analyzed by a central lab. 
Thereafter on subsequent treatment days on Week 2 to 4 during the Induction Treatment and on the 1st cycle (Week 1 to 3) during the Concomitant Treatment, only trough 
levels (predose) of sirolimus are done by local labs. 
i. 
Screening MRI scans must be performed within 21 days prior to study day 1, preferably as close to the day of enrollment as possible. Tumor evaluation by MRI will be 
performed during screening, on Day 1 and 4 weeks (±7 days) after the end of Concomitant Treatment but prior to the start of Adjuvant Treatment, and then every 8 weeks 
(± 7 days) during Adjuvant Treatment until disease progression. EOT visit MRI should be performed only for those patients that discontinue treatment for a reason other than 
disease progression. If an initial observation of objective ORR (CR or PR) is made, a confirmation scan should be done at 8 weeks after initial observation. 
j. 
Refer to treatment schema of Arm B. Induction Treatment: 4 weeks; Concomitant Treatment: 21-day cycle x2 (6 weeks); Adjuvant Treatment: 28-day cycle. 
k. 
End of Treatment Visit must occur within 4 weeks after the last dose of ABI-009. 
l. 
Follow-up for survival and initiation of anticancer therapy can be performed by telephone contact every 12 weeks (±3 weeks) or more frequently if needed, from EOT 
Visit. All patients that discontinue study drug and have not withdrawn full consent to participate in the study will continue in the follow-up phase for survival and 
anticancer therapy. This evaluation may be made by record review and/or telephone contact. 
 
 


ABI-009  
 
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Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
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52 
6. 
PROCEDURES 
6.1. 
Screening Evaluations 
Each patient who enters into the screening period for the study receives a unique patient 
identification number before any study-related procedures are performed. The patient 
identification number will be assigned. This number will be used to identify the patient 
throughout the clinical study and must be used on all study documentation related to that 
patient.  
The patient identification number must remain constant throughout the entire clinical study; it 
must not be changed after initial assignment, including if a patient is rescreened.  
Before patients may be entered into the study, the Sponsor requires a copy of the site’s written 
IRB/IEC approval of the protocol, informed consent form, and all other patient information 
and/or recruitment material, if applicable. A signed and dated Institutional Review Board (IRB) 
approved informed consent form (latest approved version) must be obtained from each patient 
prior to performing any study-specific procedures. All patients 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. The patients’ tumor samples 
will be tested to confirm diagnosis and for biomarker analyses after informed consent form has 
been signed.   
Screening evaluations will be performed for all patients to determine study eligibility. These 
evaluations must be obtained ≤21 days prior to enrollment unless otherwise specified. Any 
questions regarding patient eligibility should be directed to Aadi or other Aadi-nominated 
representatives or designees for approval. 
The following procedures are to be completed during the screening period, after signed informed 
consent has been obtained (within 21 days of treatment initiation), designated in the Schedule 
of Assessments tables. 
• Demographics (date of birth, sex, race, and ethnicity) 
• Medical and cancer history 
• Physical examination as per standard of care  
• Vital signs (e.g., blood pressure, pulse, respiration rate, temperature), height, and 
weight 
• Prior/concomitant medication evaluation: all medications taken ≤28 days prior to 
screening  
• Prior/concurrent procedures evaluation: all procedures done ≤28 days prior to 
screening 
• Karnofsky performance status 
• Pregnancy test (women of child-bearing potential, includes tubal ligations) 
• Pre-treatment tumor sample (archived or fresh) along with pathology report (required 
from all patients, if they are available and local regulations allow it) 


ABI-009  
 
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Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
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53 
• Local Laboratory Assessments: chemistry, complete blood count (CBC), differential, 
coagulation, HIV, HBV sAg, HBV cAb, HCV Ab, urinalysis (a urine dipstick may be used), 
fasting lipids 
• MRI, must be performed within 21 days prior to study day 1, preferably as close to the 
day of enrollment as possible 
For screening and treatment visits, the laboratory assessments may evaluate different analytes 
(see Table 4 for analyte listing).  
Table 4: 
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 
Glucose 
Differential: 
 
 
Sirolimus 
BUN 
-Neutrophils 
 
 
 
Creatinine 
-Lymphocytes 
 
 
 
Total bilirubin 
-Monocytes 
 
 
 
Alkaline phosphatase -Eosinophils 
 
 
 
AST (SGOT) 
-Basophils 
 
 
 
ALT (SGPT) 
 
 
 
 
Amylase 
 
 
 
 
Lipase 
 
 
 
 
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 the electronic case report form (eCRF). 
6.2. 
Treatment Period 
ABI-009 and combination agents that require infusion are to be administered after all other 
protocol-specified pre-dose assessments have been performed during each study visit that it is 
required. 
6.2.1. 
Day 1 of Each Cycle Assessment 
The following assessments will be performed on Day 1 of each cycle (±3 days), unless otherwise 
specified: 
• Physical examination  


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
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• Vital signs (temperature, systolic and diastolic blood pressure, and pulse) and weight 
• BSA calculation (Calculated ONLY on C1/D1; to be recalculated only if the weight 
changes by >10% in subsequent cycles  
• Concomitant medication and procedures evaluation  
• Karnofsky performance status 
• Adverse Event assessment 
• Clinical chemistry panel (including but not limited to sodium, potassium, chloride, 
glucose, alkaline phosphatase (ALP), AST/SGOT, ALT/SGPT, serum albumin) 
• CBC/differential 
• Fasting lipids:  
 Arm A: Day 1 of every even numbered cycle starting with Cycle 2;  
 Arm B: Day 1 of 1st cycle in Concomitant Treatment, and Day 1 of every odd 
numbered cycle in Adjuvant Treatment (C1, C3, and C5) 
• Blood samples for sirolimus levels by central lab are taken on  
 Day 1 of Cycle 1 in Arm A  
 Day 1 of Induction Treatment in Arm B 
 Trough blood sirolimus level (predose) by local lab only for Cycle 2 Day 1 in Arm A, 
and only for Cycle 1 Day 1 during the Concomitant Treatment in Arm B 
• Blood collection (for potential microRNA profiling, circulating tumor DNA profiling, 
and other biomarkers)  
Day 1 evaluations for Cycle 1 may be omitted if screening evaluations are performed within 72 
hours of Cycle 1 Day 1.  
6.2.2. 
Subsequent Treatment Day Assessment 
The following assessments will be performed on every subsequent treatment day of each cycle, 
unless otherwise specified: 
• Vital signs and weight 
• Concomitant medication and procedures evaluation 
• Adverse Event assessment 
• CBC/differential 
• Trough whole blood sirolimus level (predose) by local lab  
 Arm A: only for the first 2 cycles  
Arm B: for Week 2 to 4 during Induction Treatment, and for the 1st cycle during 
Concomitant Treatment 
6.2.3. 
Response Assessment  
Tumor response will be assessed by neuro-imaging of brain or spine with MRI scan according to 
RANO 2010 criteria. The same modality must be used at screening and throughout the study. 
MRI scans are to be performed at the following frequency: 
• ≤21 days prior to C1D1 (screening), preferably as close to the day of enrollment as 
possible 
• For Arm A, Cohorts 1 and 4: every 6 weeks after C1D1 (±7 days) 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
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• For Arm A, Cohorts 2, 3, and 5: every 8 weeks after C1D1 (±7 days) 
• For Arm B: 
• 
During Concomitant Treatment: Day 1 (±7 days) 
• 
4 weeks after the end of Concomitant Treatment (±7 days) and prior to the start 
of Adjuvant Treatment 
• 
During Adjuvant Treatment: every 8 weeks after C1D1 (±7 days) 
• End of Treatment Visit 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.  
At the time of disease progression, if a biopsy is performed, a tumor sample will be collected if 
available. Ensure that the surgical pathology report is submitted with the tumor tissue sample.  
6.3. 
End of Treatment Visit Assessment 
The EOT Visit is a safety follow-up visit that is to be performed within 4 weeks after the last dose 
of ABI-009. All efforts should be made to conduct this visit. If it is not possible to conduct the EOT 
Visit, documentation of efforts to complete the visit should be provided. 
The following procedures will be completed at the EOT Visit as designated in the Schedule of 
Assessments: 
• Physical examination  
• Vital signs and weight 
• Concomitant medication and procedures evaluation  
• Karnofsky performance status 
• Pregnancy test 
• Adverse Event assessment 
• Clinical chemistry panel  
• CBC/differential 
• Blood collection for potential microRNA profiling, circulating tumor DNA profiling, and 
other biomarkers 
• MRI (performed only for those patients that discontinue treatment for a reason other 
than disease progression) 
6.4. 
Follow-up Period for Survival and Initiation of Anticancer Therapy  
Post-treatment survival time and any subsequent anticancer therapy information status will be 
monitored approximately every 12 weeks (±3 weeks) from EOT Visit or more frequently as 
needed, until death, withdrawal of consent, or the study closes, whichever is earliest. This 
evaluation may be by record review and/or telephone contact.  
6.5. 
Correlative Studies 
6.5.1. 
Sample Collection and Processing 
Tumor Tissue 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
Confidential and Proprietary 
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Prior to treatment: Available archival tumor tissue will be analyzed for mTOR pathway activation 
by immunohistochemistry. One FFPE block (preferred) or 20-30 unstained slides will be collected. 
Post-treatment: If additional tumor tissue is obtained as part of clinical care, attempts will be 
made to collect a portion of the tissue for molecular analysis of mTOR pathway activation. Tumor 
tissue for profiling will only be collected from excess tissue after clinical reviewed pathology. 
Blood Samples 
For sirolimus at Cmax/peak level (central lab): Postdose blood sirolimus levels are taken on Day 
1 of Cycle 1 in Arm A and Day 1 of Induction Treatment in Arm B immediately prior to the end of 
infusion (ie, at 30 mins post start of infusion). 
For sirolimus trough levels (local lab): Blood samples will be taken immediately predose starting 
at week 2 for the first 2 cycles in Arm A; and on Week 2 to 4 during the Induction Treatment and 
on the 1st cycle (Week 1 to 3) during the Concomitant Treatment in Arm B. 
For research correlative studies: Extra blood for research will be collected when blood is already 
being drawn for standard clinical care. Up to 20 mL of whole blood will be collected into anti-
coagulant containing tubes on Day 1 of each cycle and at the end of treatment visit. Blood 
specimens will be labeled with the participant’s de-identified study number and collection date 
and should be processed within 30 minutes of collection if possible. Details for processing 
specimens and storage are provided in a separate Laboratory Manual. Blood samples are 
collected for potential microRNA profiling, circulating tumor DNA profiling, and other biomarkers 
for tumor burden, changes to treatment, and correlative analyses with clinical efficacy. 
6.5.2. 
Specimen Analysis 
Analyses will be performed by the laboratory of Santosh Kesari, MD, Ph.D., in the John Wayne 
Cancer Institute or other provider as agreed upon with Aadi. 
Molecular pathology analysis of tumor tissue may be performed as part of standard clinical care 
in a CLIA-certified laboratory. Results of any these clinical assays (such as EGFR, MGMT, IDH1, 
HER2, and other aberrations) will be collected for the study so that it may be associated with the 
participant's research data. Results should be obtained from analyses performed on tumor tissue 
collected prior to study treatment, and when available, analyses performed on tumor tissue 
collection post-study treatment. 
Molecular phenotyping of tumor tissue may also include the following and/or other markers as 
scientifically appropriate: PTEN, mTOR, phosphor-mTOR, pAkt, p-S6, and p-4EBP1 by 
immunohistochemistry. Blood samples will be analyzed by local lab for sirolimus levels following 
weekly ABI-009 treatment.  
Blood samples collected for future studies that may include analysis of kinase activation markers 
and signaling pathways, microRNA profiling, circulating tumor cells, cell free nucleic acids, and/or 
additional analyses performed according to new findings. 
6.5.3. 
Specimen Banking 
Patient samples collected for this study will be retained at the John Wayne Cancer Institute 
(Santosh Kesari Laboratory) for the analyses described above and for future cancer research. 


ABI-009  
 
Aadi Bioscience 
Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
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57 
Specimens will be stored indefinitely or until they are used up.  Samples will be labeled with the 
patient’s de-identified study number and collection date.  The link between study number and 
medical record number will be viewed over a password secured encrypted server-client.   
The study research coordinator will review the patient's medical record for demographic and 
clinical information pertaining to the patient's general medical history, diagnosis, and outcomes 
of any treatments received.  Samples and data extracted from the patient's medical record will 
be coded with a de-identified study number, and the patient's name and identifying information 
will be removed.  A log that links the patient's name and identifiers to the study number will be 
maintained in a secure database distinct from the secure database into which the patient's 
clinical information will be entered by study personnel. 
Dissemination of specimens for research is at the discretion of the Principal Investigator. 
Potential research collaborators outside of JWCI who approach the Institute for clinical 
specimens will be required to complete an agreement (Material Transfer Agreement or recharge 
agreement) stating that the specimens will only be released for use in disclosed research, and 
any specimen left over from research will either be returned to the Institute or destroyed.  Any 
data obtained from the use of clinical specimen will be the property of JWCI for publication and 
any licensing agreement will be strictly adhered to.  These outside collaborators may include for-
profit biotechnology corporations interested in collaborating with JWCI investigators in research 
diagnostic, prognostic assays and drug development.   
The specimens and their derivatives may have significant therapeutic or commercial value.  The 
Informed Consent form contains this information and informs the patient that there is the 
potential for financial gain by JWCI, the investigator or a collaborating researcher or entity. 
If patients later decide they do not want their specimens collected to be used for future research, 
they may tell this to the Principal Investigator who will use his best efforts to stop any additional 
studies and to destroy the specimens. Samples stored in the Kesari lab will be destroyed; for 
samples that have been disseminated outside of the Kesari lab, the Principal Investigator will 
contact the recipient to notify them of the need to halt further research and destroy specimens. 
 
 


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Protocol: GBM-007 Amd 3.0 (Dec 2, 2019) 
IND 138432 
 
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7. 
DESCRIPTION OF STUDY TREATMENTS 
7.1. 
Study Treatment Schedule 
7.1.1. 
Arm A Treatments 
Patients with recurrent HGG will enroll sequentially to Arm A from Cohort 1 through 5 in groups 
of 3 patients (Figure 4). After the enrollment of 3 patients in the previous cohort, enrollment in 
subsequent cohorts can start. Patient will be assigned to the cohort that is open at the time of 
enrollment and may not be enrolled in more than 1 cohort. Table 5 summarized treatment 
regimens per cohort. If a patient is not eligible for enrollment into the next cohort due to prior 
exposure to therapy, he/she is allowed to be enrolled in a subsequent cohort if the patient 
meets all other inclusion criteria. If the drug supply to a cohort is delayed or limited, an eligible 
patient can be enrolled into the next cohort. 
Cohort 1: ABI-009 
ABI-009 will be administered IV at 100 mg/m2 as a 30-minute IV infusion on Days 1 and 8 of every 
21-day cycle. Two dose reduction levels will be allowed: 75 mg/m2 and 60 mg/m2. 
Cohort 2: ABI-009 + TMZ 
ABI-009 will be administered IV at 60 mg/m2 as a 30-minute infusion on Days 1, 8, and 15 of every 
28-day cycle. If ABI-009 is well tolerated (no DLTs, dose modifications, or dose delays) at 60 
mg/m2 in the first 3 patients in the cohort, the dose may be increased to 75 mg/m2 for subsequent 
patients in the cohort. Intrapatient dose escalation is not allowed. Three dose reduction levels 
will be allowed: 45, 30, and 20 mg/m2. TMZ will be administered PO at 50 mg/m2 daily. 
Cohort 3: ABI-009 + BEV 
ABI-009 will be administered IV at 60 mg/m2 as a 30-minute infusion on Days 1, 8, and 15 of every 
28-day cycle. If ABI-009 is well tolerated (no DLTs, dose modifications, or dose delays) at 60 
mg/m2 in the first 3 patients in the cohort, the dose may be increased to 75 mg/m2 for subsequent 
patients in the cohort. Intrapatient dose escalation is not allowed. Three dose reduction levels 
will be allowed: 45, 30, and 20 mg/m2. 
Bevacizumab will be administered as an IV infusion (90 minutes 1st dose, 60 minutes 2nd dose and 
30 minutes afterward assuming tolerability) at a fixed dose of 5 mg/kg on Days 1 and 15 of every 
28-day cycle.  Bevacizumab will be administered approximately 10 minutes after the end of the 
ABI-009. 
Cohort 4: ABI-009 + CCNU 
ABI-009 will be administered IV at 60 mg/m2 as a 30-minute IV infusion on Days 1 and 8 of every 
21-day cycle. If ABI-009 is well tolerated (no DLTs, dose modifications, or dose delays) at 60 
mg/m2 in the first 3 patients in the cohort, the dose may be increased to 75 mg/m2 for subsequent 
patients in the cohort. Intrapatient dose escalation is not allowed. Three dose reduction levels 
will be allowed: 45, 30, and 20 mg/m2. 
Lomustine (CCNU) will be administered PO at 90 mg/m2 on Day 1 of each odd cycle. 
Cohort 5: ABI-009 + MRZ 


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ABI-009 will be administered IV at 60 mg/m2 as a 30-minute infusion on Days 1, 8, and 15 of every 
28-day cycle. If ABI-009 is well tolerated at 60 mg/m2 in the first 3 patients in the cohort, the dose 
may be increased to 75 mg/m2. Three dose reduction levels will be allowed: 45, 30, and 20 
mg/m2. 
MRZ will be administered at 0.8 mg/m2 as a 10-minute IV infusion on Days 1, 8, and 15 of every 
28-day cycle. MRZ will be administered approximately 10 minutes after the end of the ABI-009 
infusion.   
Figure 4: 
Overall Treatment Scheme 
 
Table 5:  
Arm A Study Treatment Regimens Per Cohort 
Cohort 
Agent 
Dose 
Route 
Schedule 
Cycle length 
Cohort 1 
ABI-009 
100 mg/m2 
IV 
Days 1 and 8 
21 days 
Cohort 2 
ABI-009 
60 mg/m2 
IV 
Days 1, 8, 15 
28 days 
TMZ 
50 mg/m2 
PO 
daily 
Cohort 3 
ABI-009 
60 mg/m2 
IV 
Days 1, 8, 15 
28 days 
BEV 
5 mg/kg 
IV 
Days 1 and 15 
Cohort 4 
ABI-009 
60 mg/m2 
IV 
Days 1 and 8 
21 days 
CCNU 
90 mg/m2 
PO 
Day 1 odd cycles 
Cohort 5 
ABI-009 
60 mg/m2 
IV 
Days 1, 8, 15 
28 days 
MRZ 
0.8 mg/m2 
IV 
Days 1, 8, 15 


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For Arm A, patients will continue to receive 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. 
7.1.2. 
Arm B Treatments 
The treatment scheme for Arm B is presented in Figure 5. 
 
Figure 5:  
Treatment Scheme for Arm B (Newly Diagnosed Glioblastoma) 
 
Induction Treatment: ABI-009 
Induction Treatment will start at least 3-8 weeks following surgical resection of ndGBM and after 
the surgical wound is fully healed.  
• ABI-009 will be administered IV at 60 mg/m2 as a 30-minute IV infusion every week for 4 
weeks. Three dose reduction levels will be allowed: 45, 30, and 20 mg/m2. 
Concomitant Treatment: ABI-009 + TMZ + RT 
Concomitant Treatment will start 1 week after the completion of Induction Treatment and will 
last for 6 weeks.  


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• ABI-009 will be administered IV at 60 mg/m2 as a 30-minute IV infusion on Days 8 and 15 
of every 21-day cycle. Three dose reduction levels will be allowed: 45, 30, and 20 mg/m2. 
• TMZ will be administered at 75 mg/m2 PO daily for 6 weeks as part of routine therapy for 
GBM.  
• Focal RT will be given daily at 30 x 200 cGy, 5 days/week for a total dose of 60 Gy (or 
equivalent regimens as per RTOG guidelines) as part of routine therapy for GBM. 
Adjuvant Treatment: ABI-009 + TMZ 
Adjuvant Treatment will start 4 weeks after the completion of Concomitant Treatment (any time 
during the 4th week) and will last for 24 weeks.  
• ABI-009 will be administered IV at 60 mg/m2 as a 30-minute IV infusion on Days 1, 8, and 
15 of every 28-day cycle for 6 cycles. Three dose reduction levels will be allowed: 45, 30, 
and 20 mg/m2. 
• TMZ will be administered at 150 mg/m2 PO daily on Days 1-5 of every 28-day cycle for 6 
cycles. In the absence of toxicity, TMZ may be administered at 200 mg/m2/day starting in 
Cycle 2. 
Enrollment to Arm B will be stopped, and the overall safety of adding ABI-009 to upfront standard 
of care (ie, surgery, RT, and temozolomide) will be re-assessed according to the following rules: 
• If ≥2 of the first 6 patients are unable to start RT after induction treatment with ABI-009 
at 60 mg/m2, the dose and/or dosing frequency of ABI-009 will be reduced. 
• If after dose and dosing frequency adjustment of the induction treatment with ABI-009, 
≥2 of the next 6 patients in the study are unable to start RT after induction treatment with 
ABI-009, then induction treatment with ABI-009 will be eliminated, and subsequent 
patients in Arm B will be allowed to receive only concomitant and adjuvant treatment 
with ABI-009 as outlined in Figure 5. 
• If ≥2 of the first 6 patients are unable to complete ≥75% of the planned RT due to toxicity 
related to ABI-009, the dose of ABI-009 will be reduced. 
• If after dose reduction, ≥2 of the next 6 patients in the study are unable to complete ≥75% 
of the planned RT due to toxicity related to ABI-009, enrollment to Arm B will be stopped 
and the overall safety of adding ABI-009 to upfront standard of care will be re-assessed. 
 
 
7.2. 
Definition of Dose-limiting Toxicity (DLT) 
Toxicity 
grading 
is 
based 
on 
NCI-CTCAE 
v5.0, 
available 
at 
the 
website 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
A DLT is defined as 1 or more of the following that occurs within the first 28 days of treatment 
and is considered possibly, probably or definitely related to ABI-009, or the combination of ABI-
009 with TMZ, BEV, or CCNU administration: 
• Grade 4 neutropenia  
• Grade 3 or higher febrile neutropenia; 


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• Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding; 
• Grade 3 non-hematologic toxicity (with exception of sub-optimally managed 
diarrhea, nausea and vomiting) that persists for >7 days* 
• Grade 3 nausea, diarrhea, and vomiting lasting ≥5 days 
• Grade 3 creatinine increase that persists ≥5 days* despite adherence to hydration 
guidelines; 
• Any ≥grade 2 non-hematological toxicity requiring a dose delay of >2 weeks despite 
appropriate symptomatic therapy. 
*  verified by repeat assessment 
Temozolomide dose reduction or interruption as described below will not necessarily constitute 
a DLT with respect to ABI-009 unless the AE, in particular myelotoxicity, is above and beyond that 
expected for TMZ with or without radiotherapy. The same rule applies for BEV and CCNU. 
7.3. 
Dosing Delays and Dose Modifications Due to Toxicity 
7.3.1. 
ABI-009 Schedule Adjustments for Toxicity 
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 on Day 1 of each cycle, patients 
must meet the following hematological requirements: 
• ANC ≥1.5 x 109/L 
• Platelet count ≥100 x 109/L 
• Hemoglobin ≥9 g/dL 
Patients who experience a DLT at least possibly attributed to ABI-009 may continue treatment at 
the next lower dose level until disease progression or unacceptable toxicity.  Once the dose has 
been reduced for a patient, it may not be escalated.  Provisions are not made for dose levels 
below Dose Level -2; if Dose Level -2 is not acceptable for a particular patient, ABI-009 will be 
permanently discontinued for the patient. 
Approval from the Medical Monitor is required to restart study treatment after interruption of a 
duration of one cycle (ie, 28 days for a 28-day cycle, 21 days for a 21-day cycle). Patients with 
ABI-009 discontinued due to dose limiting toxicities will be removed from the study (unless 
approved by Medical Monitor) and continue with safety follow-up. In combination cohorts, if ABI-
009 is discontinued, the patient may continue to receive the combination agent as part of routine 
medical management but will be removed from the treatment portion of this study. 
7.3.2. 
Dose Modification Guidelines for ABI-009 
Doses will be reduced for hematologic and other toxicities. Dose modifications are permitted 
according to the criteria below. Dose reductions will occur sequentially, there should be no direct 
reduction by two dose levels. For planned ABI-009 dose of 100 mg/m2, the reduced dose levels 
allowed are 75 mg/m2 and 60 mg/m2. For planned ABI-009 dose of 60 mg/m2, the reduced dose 
levels allowed are 45, 30, and 20 mg/m2.  Dose adjustments are to be made according to the 
system showing the greatest degree of toxicity. 


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In the event of clinically significant AE in any part of the study, treatment may be withheld, and 
supportive therapy administered as clinically indicated. If the toxicity or event is not grade 3/4 
and resolves to baseline or grade 1 in less than or equal to 14 days of stopping therapy, then 
treatment may be restarted. Dose reduction of ABI-009 should be considered as clinically 
indicated. 
If the toxicity does not resolve to at least grade 1 in less than 14 days, withdrawal from treatment 
with the ABI-009 is recommended. However, if the investigator and Aadi Medical Monitor agree 
that further treatment would benefit the patient, treatment can continue with at least one dose 
level dose reduction, per Table 6. 
Table 6:  
Dose Level Reduction Guidelines for ABI-009 
Dose level 
ABI-009 Dose 
0 
Initial Dose: 100 mg/m2 
Initial Dose: 60 mg/m2 
-1 (first dose reduction) 
75 mg/m2 
45 mg/m2 
-2 (second dose reduction) 
-3 (third dose reduction) 
60 mg/m2 
NA 
30 mg/m2 
20 mg/m2 
Any patient meeting the criteria for Hy’s Law case (i.e. severe drug-induced liver injury) will be 
considered a dose-limiting toxicity. A Hy’s Law case is defined as: AST or ALT values of ≥3 x ULN 
AND with serum total bilirubin level (TBL) of >2 x ULN without signs of cholestasis and with no 
other clear alternative reason to explain the observed liver-related laboratory abnormalities. 
ABI-009 dose modification guidelines are outlined in Table 7 for clinically significant toxicities that 
are deemed related. Adverse events considered for dose reduction should not include the events 
assessed by the investigator as exclusively related to underlying disease or other medical 
condition or concomitant treatment. 
Table 7:  Dose Modification Algorithms for Adverse Events Possibly Related to ABI-009 
System/Organ 
Adverse Event 
CTCAE Grade 
v5.0 
Dose modification Algorithm 
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. 
Grade ≥3 
Hold ABI-009 until resolution to Grade 1 or baseline and 
restart at the same dose for 1st occurrence for subsequent 
occurrences, drug will be restarted at a reduced dose; provide 
supportive care as clinically indicated. 
Skin and 
Subcutaneous 
Tissue 
Disorders 
Skin rash 
Grade 2 
Tolerable: Continue ABI 009 at full dose, monitor as clinically 
indicated 
Intolerable: Hold ABI-009 until resolution to Grade 1 or 
baseline and restart at the same dose for 1st occurrence; for 
subsequent occurrences, drug will be restarted at a reduced 
dose; provide supportive care as clinically indicated. 


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System/Organ 
Adverse Event 
CTCAE Grade 
v5.0 
Dose modification Algorithm 
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. 
Gastrointestin
al 
Disorders 
Diarrhea 
despite 
optimal 
medication 
Grade 2 
Hold ABI-009 until resolution to Grade 1 or baseline and 
restart at the same dose for 1st occurrences; for 2nd and 
subsequent events, drug will be restarted at a reduced dose; 
provide supportive care as clinically indicated. 
Grade ≥3 
Hold ABI-009 until resolution to Grade 1 or baseline; for 
subsequent events, drug will be restarted at a reduced dose; 
provide supportive care as clinically indicated. 
Metabolic 
disorders 
Hyperlipemia 
(cholesterol, 
triglycerides) 
Grade 3 
If this is persistent for 2 months, reduce by 1 dose level at 
start of next cycle 
Grade 4 
If this is persistent for 1 month, reduce by 1 dose level at start 
of next cycle 
Hyperglycemia 
Grades 1 
and 2 
Start at home 2x/day glucose monitoring; initiate medical 
management 
Grade 3 
Initiate medical management; If recurrent post ABI-009 
despite adequate medical management, reduce by 1 dose 
level 
Grade 4 
Initiate medical management, hold ABI-009 until grade 2 or 
less, restart 1 dose level lower 
Hematologic 
toxicity 
Thrombocytop
enia, 
Neutropenia, 
Anemia 
Grade 2 
ABI-009 can be administered if meeting the following 
hematological requirements: ANC >1.5 x 109/L, platelets >100 
x 109/L and hemoglobin ≥9 g/dL 
Grade ≥3 
Hold ABI-009 immediately for the remainder of that cycle.  
Repeat blood collection within 3 days.  ABI-009 can resume 
once meeting following requirements: ANC >1.5 x 109/L, 
platelet count >100 x 109/L and hemoglobin ≥9 g/dL. For 2nd 
and subsequent events, drug will be restarted at a reduced 
dose; G-CSF may be given as deemed indicated. 
Respiratory 
events 
Pneumonitis, 
bronchiolitis 
obliterans, 
and/or 
organizing 
pneumonia 
Grade 2  
Hold ABI-009 immediately for up to 3 weeks until resolved to 
≤ grade 1, then reduce by 1 dose level. If it is still a Grade 2 
after 3 weeks, discontinue treatment. If > Grade 2 recurs after 
resuming ABI-009 at a reduced dose level, discontinue 
treatment. 
For noninfectious pneumonitis, if cough is troublesome, 
prescribe corticosteroids. 
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 


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System/Organ 
Adverse Event 
CTCAE Grade 
v5.0 
Dose modification Algorithm 
withdrawn from the study if they fail to recover to ≤ grade 1 
within 3 weeks. 
For grade 4 noninfectious pneumonitis, discontinue ABI-009. 
a 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. 
7.3.3. 
Temozolomide Arm A Schedule Adjustment for Toxicity 
Prior to TMZ administration on Day 1 of each cycle, or following TMZ interruption, patients must 
meet the following hematological requirements: 
• ANC ≥1.5 x 109/L 
• Platelet count ≥100 x 109/L 
The treatment will be on hold up to 14 days until the patient has fulfilled these criteria. 
Temozolomide is administered at 50 mg/m2 daily, with one dose reduction to 37.5 mg/m2 
allowed for toxicity (Table 8).  
Table 8: 
Dose Level Reduction Guidelines for TMZ 
Dose level 
TMZ Dose 
-1 (dose reduction) 
37.5 mg/m2 
0 
Initial Dose: 50 mg/m2 
Temozolomide dose modification guidelines are outlined in Table 9 for clinically significant 
toxicities that are deemed related. If TMZ is discontinued, patients may continue to receive ABI-
009 and remain on the treatment portion of this study. 
Table 9: 
Dose Modifications for Adverse Events Possibly Related to TMZ (Arm A) 
Toxicity 
Reduce TMZ by 1 Dose 
Level  
Discontinue TMZ 
Absolute Neutrophil Count 
< 1.0 x 109/L 
If dose reduction < 37.5 mg/m2 required; or if same 
Grade 3 nonhematological toxicity (except alopecia, 
nausea, vomiting) recurs after dose reduction 
Platelet Count 
≥ 10 x 109/L and < 100 
x 109/L 
Nonhematological Toxicity  
(except alopecia, nausea, 
vomiting) 
Grade 3 
Grade 4 
 
7.3.4. 
Temozolomide Arm B Schedule Adjustment for Toxicity 
If treatment cannot be administered on the planned visit date, TMZ may be administered ±3 days 
from the scheduled date. Prior to TMZ administration on Day 1 of each cycle, or following TMZ 
interruption, patients must meet the following hematological requirements: 
• ANC ≥1.5 x 109/L 
• Platelet count ≥100 x 109/L 


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The following TMZ modifications are provided as guidelines that may be used as appropriate or 
modified as per local institutional practice. During concomitant radiotherapy, TMZ is 
administered at 75 mg/m2 PO daily. TMZ dosing should be interrupted or discontinued during 
concomitant phase according to the hematological and nonhematological toxicity criteria as 
noted in Table 10. 
Table 10: 
Temozolomide Dose Modifications During Concomitant Treatment with 
Radiotherapy (Arm B) 
Toxicity 
TMZ Interruption 
TMZ Discontinuation 
Absolute Neutrophil Count 
≥0.5 x 109/L and <1.5 x 109/L 
<0.5 x 109/L 
Platelet Count 
≥10 x 109/L and <100 x 109/L 
<10 x 109/L 
Nonhematological Toxicity (except for 
alopecia, nausea, vomiting) 
Grade 2 
Grade 3 or 4 
 
During adjuvant treatment, TMZ is administered at 150 mg/m2/day on Day 1-5 of every 28-day 
cycle for 6 cycles. In the absence of toxicity, TMZ may be administered at 200 mg/m2/day starting 
in Cycle 2. Dose reduction or discontinuation during Adjuvant Treatment should be applied 
according to Table 11 and Table 12. If TMZ is discontinued, patients may continue to receive ABI-
009 and remain on the treatment portion of this study. 
 
Table 11: 
Temozolomide Dose Levels for Adjuvant Treatment (Arm B) 
Dose level 
TMZ Dose (mg/m2/day) 
Remarks 
-1 
100 
Reduction for prior toxicity 
0 
150 
Dose during Cycle 1 
1 
200 
Dose for Cycles 2+ in absence of toxicity 
 
Table 12: 
Temozolomide Dose Modifications During Adjuvant Treatment (Arm B) 
Toxicity 
Reduce TMZ by 
1 Dose Level  
Discontinue TMZ 
Absolute Neutrophil Count 
<1.0 x 109/L 
If dose reduction <100 mg/m2 required; or if same grade 3 
nonhematological toxicity (except alopecia, nausea, 
vomiting) recurs after dose reduction 
Platelet Count 
≥10 x 109/L and 
<100 x 109/L 
Nonhematological Toxicity 
(except alopecia, nausea, 
vomiting) 
Grade 3 
Grade 4 
 


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7.3.5. 
MRZ Schedule Adjustment for Toxicity 
If treatment cannot be administered on the planned visit date, MZB may be administered +/- 3 
days from the scheduled date. Prior to MRZ administration on Day 1 of each cycle, patients must 
meet the following hematological requirements: 
• Creatinine ≤ 1.5 x ULN 
• Hemoglobin ≥ 8 g/dL 
• Platelet count ≥ 75 x 109/L 
The treatment will be on hold up to 14 days until the patient has fulfilled these criteria.  
Patients who experience a DLT at least possibly attributed to MRZ may continue treatment at the 
next lower dose level (see Table 15 below) until disease progression or unacceptable toxicity.  
Once the dose has been reduced for a patient, it may not be escalated.  Provisions are not made 
for dose levels below Dose Level -2; if Dose Level -2 is not acceptable for a particular patient, MRZ 
will be permanently discontinued for the patient. 
Day 1 Dose Missed 
If the dose held or missed was to be given on Day 1 of the next cycle, that next cycle will not be 
considered to start until the day the first dose is actually administered to the patient (i.e., D1-D8-
D15-Rest, X-D1-D8-D15-Rest, etc.). 
Day 8 Dose Missed 
Cycle continues per protocol, with one dose not given (i.e., D1-D8-D15-Rest, D1-X-D15-R, D1-D8-
D15-Rest, etc.). Day 15 is administered as per cycle calendar if counts and chemistries permit. 
Day 15 Dose Missed 
That week becomes the week of rest. Next dose (if counts and chemistries permit) becomes Day 
1 of a new cycle (i.e., D1-D8-D15-Rest, D1-D8-X, D1-D8-D15-Rest, etc.).   
Approval from the Medical Monitor is required to restart study treatment after interruption of a 
duration of one cycle. 
7.3.6. 
Dose Reduction Guidelines for MRZ 
In the event of clinically significant AE in any part of the study, treatment may be withheld, and 
supportive therapy administered as clinically indicated. If the toxicity or event is not grade 3/4 
and resolves to baseline or grade 1 in less than or equal to 14 days of stopping therapy, then 
treatment may be restarted. Dose reduction (Table 13) of MRZ should be considered as clinically 
indicated. 
Table 13: 
Dose Level Reduction Guidelines for MRZ 
Dose level 
MRZ Dose 
0 
Initial Dose: 0.8 mg/m2 
-1 (first dose reduction) 
0.7 mg/m2 
-2 (second dose reduction) 0.55 mg/m2 


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MRZ dose modification guidelines are outlined in Table 14 for clinically significant toxicities that 
are deemed related. If MRZ is discontinued, patients may continue to receive ABI-009 and remain 
on the treatment portion of this study. 
 
Table 14: 
MRZ Dose Modification 
Toxicity 
MRZ Dose Modifications & Actions 
Grade 2 Central Nervous System AEs or moderately 
severe Hallucinations* related to MRZ 
Consider holding MRZ until toxicity resolves. When 
toxicity resolves, consider reinitiating with reduced 
dose of MRZ to be determined in discussion with the 
Medical Monitor, but usually to the level of the next 
lower dose cohort. 
Grade 3 Central Nervous System AEs related to MRZ 
Other Grade 3 AEs related to MRZ 
Grade 4 Hematologic or Severe Hallucinations* related 
to MRZ 
Hold MRZ until toxicity resolves. When toxicity 
resolves, may reinitiate with reduced dose of MRZ to 
be determined in discussion with the Medical 
Monitor, but usually to the level of the next lower 
dose cohort. 
Grade 4 Nonhematological or Extremely Severe 
Hallucinations* related to MRZ 
Generally discontinue all study treatment. Exceptions 
may be discussed with the Medical Monitor for 
approval if it is determined by the investigator that re-
initiation at a lower dose may be appropriate based 
on clinical judgment. 
AE related to MRZ that requires a dose delay > 14 days 
Consider reinitiating with reduced dose of MRZ to be 
determined in discussion with the Medical Monitor, 
but usually to the level of the next lower dose cohort. 
Prior to initiation of subsequent cycles, reassessment 
of safety laboratory tests is required for liver 
functions tests (LFTs), serum creatinine, and complete 
blood count. 
*Hallucinations are defined as follows: 
Very mild:  
While resting or going to sleep, sees visions, smells odors or hears voices, sounds, 
or whispers in the absence of external stimulation, but no impairment in 
functioning. 
Mild:  
While in a clear state of consciousness, hears a voice calling the individual's name, 
experiences non-verbal auditory hallucinations (e.g., sounds or whispers), formless 
visual hallucinations or has sensory experiences in the presence of a modality 
relevant stimulus (e.g., visual illusions) infrequently (e.g., 1-2 times per week) and 
with no functional impairment. 
Moderate:  
Occasional verbal, visual, gustatory, olfactory or tactile hallucinations with no 
functional impairment OR non-verbal auditory hallucinations/visual illusions more 
than infrequently or with impairment. 
Moderately Severe:  Experiences daily hallucinations OR some areas of functioning are disrupted by 
hallucinations. 
7.3.7. 
Bevacizumab Schedule Adjustment for Toxicity 
If treatment cannot be administered on the planned visit date, BEV may be administered ±3 days 
from the scheduled date. Dose reduction or discontinuation of BEV should be applied according 


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to Table 15 and Table 16. If BEV is discontinued, patients may continue to receive ABI-009 and 
remain on the treatment portion of this study. 
Table 15: 
Dose Level Guidelines for BEV 
Dose level 
BEV Dose (mg) 
Schedule (28-day cycle) 
-1 
7.5 
Day 1 
0 
5 
Days 1 and 15 
 
Table 16: 
Dose Modifications for Adverse Events Possibly Related to BEV 
Adverse Event 
Severity 
Dose modification Algorithm 
Gastrointestinal 
perforation 
Any 
Discontinue. 
Fistulae 
• 
Tracheoesophageal fistula, any grade 
• 
Fistula Grade 4 
• 
Fistula formation involving any internal 
organ 
Discontinue. 
Wound healing 
complications 
• 
Wound healing complications requiring 
medical intervention 
• 
Necrotizing fasciitis 
Discontinue. 
Hemorrhage 
• 
Grade 3 or 4 
Discontinue. 
• 
Recent history of hemoptysis of 1/2 
teaspoon (2.5 mL) or more 
Withhold if not controlled with medical 
management; resume at modified dose 
once controlled. 
Hypertension 
• 
Hypertensive crisis 
• 
Hypertensive encephalopathy 
Discontinue. 
• 
Hypertension, severe 
Withhold if not controlled with medical 
management; resume at modified dose 
once controlled. 
Posterior 
reversible 
encephalopathy 
syndrome (PRES) 
• 
Any 
Discontinue. 
Renal toxicity and 
proteinuria 
• 
Nephrotic syndrome 
Discontinue. 
• 
Proteinuria ≥2 g/24 hours in absence of 
nephrotic syndrome 
Withhold until proteinuria less than 2 g/24 
hours. 
Infusion Reaction 
• 
Severe infusion reaction 
Discontinue. 
• 
Clinically significant 
Interrupt infusion; resume at a decrease 
rate of infusion after symptoms resolve. 
• 
Mild, clinical insignificant 
Decrease infusion rate. 
Congestive heart 
failure 
• 
Any 
Discontinue. 
 


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7.3.8. 
Lomustine (CCNU) Schedule Adjustment for Toxicity 
If treatment cannot be administered on the planned visit date, CCNU may be administered ±3 
days from the scheduled date. Prior to CCNU administration, patients must meet the following 
hematological requirements: 
• Leukocytes ≥4.0 x 103/uL 
• Platelet count ≥100 x 109/L 
Table 17: 
Dose Level Guidelines for CCNU 
Dose level 
CCNU Dose (mg/m2) 
Schedule (21-day cycle) 
0 
90 
Days 1 of each odd cycle (once every 6 weeks) 
The treatment may be held until hematological requirements are met. If CCNU is not tolerated 
at 90 mg/m2, there will be no further dose reduction and CCNU will be discontinued. If CCNU is 
discontinued, patients may continue to receive ABI-009 and remain on the treatment portion of 
this study. 
7.3.9. 
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. 
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 ULN 
• AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value AST or ALT elevation 
< ULN 
≥3x ULN 
• AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or TBL 
values include, but are not limited to: 
− Hepatobiliary tract disease 
− Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, Cytomegalovirus, 
Herpes Simplex Virus, Varicella, Toxoplasmosis, and Parvovirus) 
− Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia.   
− Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms   
− Heritable disorders causing impaired glucuronidation (e.g., Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(e.g., indinavir, atazanavir) 


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− Alpha-one antitrypsin deficiency 
− Alcoholic hepatitis 
− Autoimmune hepatitis  
− Wilson’s disease and hemochromatosis 
− Nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH)  
− Non-hepatic causes (e.g., rhabdomylosis, hemolysis) 
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).   
• 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. 
 
Criteria for Rechallenge with ABI-009 After Potential Hepatotoxicity 
The decision to rechallenge the patient should be discussed and agreed upon unanimously by the 
patient, investigator, and Aadi medical monitor. 
If signs or symptoms recur with rechallenge, then ABI-009 should be permanently discontinued.  
Patients who clearly meet the criteria for permanent discontinuation (as described in Section 
7.3.1) should never be rechallenged. 
7.3.10. 
Overdose  
On a per dose basis, an overdose is defined as 10% over the protocol-specified dose 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.  


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On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified 
rate of 30 minutes for each infusion. 


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8. 
STUDY DRUG MANAGEMENT  
8.1. 
Description of Study Drugs  
8.1.1. 
ABI-009 
8.1.1.1. 
Supply and Storage 
ABI-009 is an investigational product (IP) that will be supplied by the Aadi Bioscience 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 designated study 
monitor for verification of proper study drug storage. 
8.1.1.2. 
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 and administered to the patient in 
the study site (see Pharmacy Manual). The Investigator will calculate the body surface area (BSA) 
of the patient in order to determine the total amount of ABI-009 to be administered. 
8.1.1.3. 
Receipt and Return 
The process for handling the receipt and return of the study drug supplies are described in the 
Pharmacy Manual. 
8.1.2. 
Temozolomide 
8.1.2.1. 
Supply, Storage, and Use 
Temozolomide will be obtained at the local hospital pharmacy by Investigator/physician 
prescription for standard of care therapy and used according to TMZ Product label and standard 
institutional practices. Aadi Bioscience will not be sourcing or providing temozolomide. 
Temozolomide is supplied as capsules for oral use in child-resistant sachets and should be stored 
at 25°C (77°F) with excursions permitted to 15-30°C (59-86°F). Patients will be instructed to take 
their dose as scheduled.   
8.1.3. 
Marizomib 
8.1.3.1. 
Supply and Storage 
Marizomib is an investigational product that will be provided by Celgene in drug kits contain 1 
single-use vial of lyophilized product (2 mg MRZ) along with 1 sing-use vial of 20 mL diluent. Each 


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vial will be labeled according to country-specific regulatory requirements for labeling of IPs. Vials 
should be stored upright in a refrigerator (2°-8°C; 36°-46°F). Reconstituted MRZ may be stored 
for up to 3 hours at 2-8°C (36°- 46°F), followed by 2 hours at room temperature (<25°C). 
8.1.3.2. 
Preparation and Administration 
MRZ will be reconstituted by appropriate study personnel and administered to the patient in the 
study site (see Pharmacy Manual). The Investigator will calculate the body surface area (BSA) of 
the patient in order to determine the total amount of MRZ to be administered. 
8.1.3.3. 
Hydration 
To mitigate the theoretical possibility of renal dysfunction, patients will receive approximately 
250 ml normal saline administered over approximately 30 minutes before the MRZ infusion. After 
the MRZ infusion has been completed, additional fluid may be given at the investigator’s 
discretion. 
8.1.3.4. 
Receipt and Return 
The process for handling the receipt and return of the study drug supplies are described in the 
Pharmacy Manual. 
8.1.4. 
Bevacizumab 
8.1.4.1. 
Supply and Storage 
Bevacizumab will be obtained at the local hospital pharmacy by Investigator/physician 
prescription for standard of care therapy and used according to the bevacizumab Product label 
and standard institutional practices. Aadi Bioscience will not be sourcing or providing 
bevacizumab.  Bevacizumab Injection is a clear to slightly opalescent, colorless to pale brown, 
sterile solution for intravenous infusion supplied as single-dose vials. Vial must be stored 
refrigerated at 2-8°C (36-46°F) and protect from light. Vials must not be frozen or shaken. 
Bevacizumab solution can be stored at 2-8°C (36-46°F) for up to 8 hours. 
8.1.4.2. 
Preparation and Administration 
Bevacizumab will be prepared and administered according to standard institutional practice. In 
general, the necessary amount of BEV is withdrawn from vials and diluted in a total volume of 
100 mL of 0.9% Sodium Chloride Injection (never administered or mixed with dextrose solution). 
The first infusion is administered over 90 minutes. The second infusion can be administered over 
60 minutes if the first infusion is tolerated. Subsequent infusions can be over 30 minutes of 
second infusion over 60 minutes is tolerated. 
8.1.5. 
Lomustine (CCNU) 
8.1.5.1. 
Supply, Storage, and Use 
Lomustine will be obtained at the local hospital pharmacy by Investigator/physician prescription 
for standard of care therapy and used according to CCNU Product label and standard institutional 
practices. Aadi Bioscience will not be sourcing or providing lomustine.  Lomustine is supplied as 
capsules in bottles for oral use and should be stored at 25°C (77°F) with excursions permitted to 


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15-30°C (59-86°F). Temperatures over 40°C (104°F) must be avoided. Patients will be instructed 
to take their dose as scheduled. 
8.2. 
Drug Accountability, Disposal, and Compliance 
The Investigator or designee shall record the dispensing of all study drugs to patients and any 
remaining study drug after dosing in a study Drug Accountability Record. The study drug record 
will be made available to Aadi or authorized Aadi-designated monitoring personnel for the 
purpose of accounting for the study drug supply. Inspections of the study drug supply for 
inventory purposes and assurance of proper storage will be conducted as necessary. Any 
significant discrepancy will be recorded and reported to Aadi or their designee and a plan for 
resolution will be documented. 
Accurate recording of all study drug administrations will be made in the appropriate section of 
the patient’s eCRF and source documents. The investigator or designee is responsible for 
accounting for all study-specific IP either administered or in their custody during the course of 
the study. 
8.2.1. 
ABI-009 
Upon receipt of ABI-009 supplies, the Investigator or designee will conduct an inventory and sign 
both copies of the study drug receipt and forward one copy to the address indicated on the form. 
One copy of the receipt and the packing slip must be retained in the Investigator’s regulatory file 
records. 
Only completely unused ABI-009 vials should be retained by the site until a representative from 
Aadi or Aadi-designee 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. 
A representative from Aadi or his/her designee will inspect the ABI-009 drug inventory, Drug 
Accountability Record form(s), and will arrange for the disposition of any remaining unused study 
drug. No study drug may be returned to Aadi without the representative from Aadi or other Aadi-
designated personnel first inspecting the study drug inventory and accountability 
documentation. 
8.2.2. 
Temozolomide 
Temozolomide is managed as a prescribed medication and is administered according to standard 
institutional practices. 
8.2.3. 
Marizomib 
Upon receipt of MRZ supplies, the Investigator or designee will conduct an inventory and sign 
both copies of the study drug receipt and forward one copy to the address indicated on the form. 
One copy of the receipt and the packing slip must be retained in the Investigator’s regulatory file 
records.  
Only completely unused MRZ vials should be retained by the site until a representative from Aadi 
or Aadi-designee has completed an inventory. Partially used and completely used vials should be 


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destroyed according to the site’s guidelines, and their disposition should be recorded on the 
Investigational Drug Accountability Record Form. 
8.2.4. 
Bevacizumab 
Bevacizumab is managed as a prescribed medication and is administered according to standard 
institutional practices. 
8.2.5. 
Lomustine (CCNU) 
Lomustine is managed as a prescribed medication and is administered according to standard 
institutional practices. 
 


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


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Strong CYP3A4 Inhibitor 
Strong CYP3A4 Inducer 
clarithromycin 
indinavir 
itraconazole 
ketoconazole 
nefazodone 
ritonavir 
saquinavir 
suboxone 
telithromycin 
barbiturates 
carbamazepine 
efavirenz 
glucocorticoids 
modafinil 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifabutin 
St. John's Wort 
troglitazone 
• Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to receiving the 
first dose of ABI-009 is prohibited as inhibitors and inducers of CYP3A4 may affect ABI-
009 metabolism and/or increase toxicities.  
• 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. 
 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Study Populations 
The Safety population (Full Analysis Dataset) will consist of all patients who have received at least 
one dose of ABI-009. The efficacy-evaluable population (Efficacy Analysis Dataset) will consist of 
all patients who received at least two cycles of ABI-009 and underwent a post-treatment disease 
assessment or who received at least one dose of ABI-009 and withdrew from the study prior to 
completion of 2 full cycles due to progressive disease, death or drug-related toxicity. A patient 
who is removed from the study because of disease progression, death or drug-related toxicity 
prior to the end of cycle 2 will be included in the efficacy-evaluable patient population. 
The primary efficacy analysis will be performed in the Efficacy Analysis Dataset and the Full 
Analysis Dataset. Safety analyses will be performed in the Full Analysis Dataset. 
10.2. 
Primary Endpoint 
The primary endpoint is ORR by independent radiologic review and is defined as the proportion 
of patients who achieve a confirmed PR or CR per RANO 2010 criteria.  
For Arm A, Cohort 2, 3, and 5, tumor response, including CR, PR, SD, or PD, will be assessed with 
MRI imaging every 8 weeks.   
For Arm A, Cohorts 1 and 4, tumor response will be assessed with MRI imaging every 6 weeks. 
For Arm B, tumor response will be assessed with MRI imaging on Day 1 and at the end of Week 
6 during Concomitant Treatment, and then every 8 weeks (± 7 days) during Adjuvant Treatment 
until disease progression. 
10.2.1. 
Power and Sample Size for Primary Endpoint 
Simon's two-stage design (Simon, 1989) will be used for Arm A of this study. The null hypothesis 
that the true response rate is 15% will be tested against a one-sided alternative. In the first 
stage, 9 patients will be accrued. If there are 1 or fewer responses in these 9 patients, the study 
will be stopped. Otherwise, 10 additional patients will be accrued for a total of 19. The null 
hypothesis will be rejected if 6 or more responses are observed in 19 patients. This design yields 
a type I error rate of 0.0497 and power of 0.8132 when the true response rate is 40%.  Arm B of 
the study will enroll 19 patients as an exploratory analysis to obtain a signal of efficacy. 
10.3. 
Secondary Endpoints 
Demographic and baseline measurement variables will be summarized. Compliance to the study 
schedule will be evaluated and any deviation from the schedule of treatment will be recorded. 
The percentage of patients failing to complete the study or discontinuing prematurely (as well as 
the times and reasons for discontinuation) will be displayed, along with the time and reason for 
discontinuation.  
10.3.1. 
Secondary Efficacy Assessments 
The analysis of PFS rate at 6 months, PFS rate at 12 months, median PFS, and median OS will be 
conducted on the Efficacy Analysis Dataset. A sensitivity analysis will also be conducted using the 


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Full Analysis Dataset. Progression-free survival at 6 months, PFS at 12 months, median PFS, OS at 
12 months, and OS for patients will be summarized using KM methods.  
Progression-free survival is defined as the time from the first dose date to the first observation 
of a disease progression or death due to any cause. If a patient has not progressed or died by the 
data cutoff date, the PFS time will be censored at the time of the last evaluable tumor 
assessment.  
Overall survival is defined as the time from the first dose date to the date of death due to any 
cause. If a patient is lost to follow-up before the data cutoff date or still alive by the data cutoff 
date the OS time will be censored at the last contact date. 
Secondary efficacy endpoints will consist of the following for both Arm A and Arm B: 
• PFS at 6 months 
• PFS at 12 months 
• PFS 
• OS at 12 months 
• OS 
After disease progression, patients in both Arms A and B will be followed for survival every 12 
weeks, or more frequently as needed, until death, withdrawal of consent, or the study closes, 
whichever is the earliest.  
10.4. 
Safety Assessments 
All patients will be evaluated for safety analysis if they receive at least one dose of ABI-009. 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. Adverse events will be grouped by their system organ class and 
preferred term. Summary tables will include the number and percentage of patients with AEs, 
SAEs, fatal AEs and other AEs of interest. 
Physical examination, vital sign, laboratory assessments (e.g., serum chemistry, hematology), and 
KPS performance status will be monitored. All SAEs (regardless of relationship to IP) will be 
followed until resolution. Laboratory analysis will be performed as per study schedule. 
10.5. 
Exploratory Endpoints 
Exploratory studies will be performed in consenting patients to gain a more in-depth 
understanding of molecular profiling and mTOR pathway status in this patient population. 
Assessment of pre-treatment archived tumor samples and sirolimus levels following weekly ABI-
009 treatment will be performed for molecular information, including but not limited to the 
activity of mTOR pathway, and correlation with activity/tolerability to ABI-009 treatment. These 
exploratory studies are not designed to meet statistical significance and data from these studies 
will be summarized using descriptive statistics, including number of patients (N), mean, standard 
deviation (SD), median, and coefficient of variation (CV). As necessary, more definitive statistical 


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methods can be applied to evaluate apparent trends. Subgroup analyses will be performed as 
appropriate.  
A logistic regression model will be used to identify biomarkers for responders and non-
responders. Cox models will be used to explore the association between these molecular 
phenotypes and duration of PFS and overall survival.  Multiple adjustments will not be performed 
for this analysis and, therefore, these studies are considered exploratory. 
Tissue sampling at additional time points is not required, but if additional tissue is obtained as 
part of clinical care during the treatment portion of the study or following progression and it is 
possible to obtain molecular information on that tissue, the information will be collected for the 
study. Possible effects of ABI-009 treatment on these markers (change from baseline) will be 
assessed if post-treatment tissue specimen(s) are available. 
Blood samples are collected for potential microRNA profiling, circulating tumor DNA profiling, 
and other biomarkers for tumor burden, changes to treatment, and correlative analyses with 
clinical efficacy. 


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11. 
MONITORING, RECORDING AND REPORTING OF ADVERSE EVENTS  
11.1. 
Adverse Events 
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a patient during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the patient’s health, including 
laboratory test values (as specified by the criteria below), regardless of etiology. Any worsening 
(i.e., any clinically significant adverse change in the frequency or intensity of a preexisting 
condition) should be considered an AE. A diagnosis or syndrome should be recorded on the AE 
page of the eCRF rather than the individual signs or symptoms of the diagnosis or syndrome. 
Note: Disease progression and death due to disease will not be recorded as an AE. 
Abuse, withdrawal, sensitivity or toxicity to the IP should be reported as an AE. Overdose, 
accidental or intentional, whether or not it is associated with an AE should be reported on the 
appropriate CRF, see Section 7.3.10 for the definition of overdose. Any sequela of an accidental 
or intentional overdose of the IP should be reported as an AE on the AE CRF. If the sequela of an 
overdose is an SAE, then the sequela must be reported on an SAE report form and on the AE CRF. 
The overdose resulting in the SAE should be identified as the cause of the event on the SAE report 
form and CRF but should not be reported as an SAE itself.  
All patients will be monitored for AEs during the study. Assessments may include monitoring of 
any or all of the following parameters: the patient’s clinical symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or other appropriate tests and 
procedures. 
All AEs will be recorded by the investigator from the time the patient signs informed consent until 
28 days after the last dose of ABI-009 and/or combination agent, and those SAEs made known to 
the investigator at any time thereafter that are suspected of being related to IP. AEs and SAEs 
will be recorded on the AE page of the eCRF and in the patient’s source documents. All SAEs must 
be reported to Aadi Drug Safety within 24 hours of the investigator’s knowledge of the event by 
facsimile, or other appropriate method, using the SAE Report Form, or approved equivalent form. 
The investigator’s clinical judgment is used to determine whether a patient is to be removed from 
treatment due to an AE. The investigator is responsible for ensuring that all AEs observed by the 
investigator or reported by the patient that occur after the first dose of IP through the EOT Visit 
are reported using the applicable eCRF (eg, AE Summary CRF).  
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] 
• Seriousness 
• Assessment of relatedness to the study agents 
• 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.  
11.2. 
Prior Experience 
Expected events are those that have been previously identified as resulting from administration 
of the agent. An AE is considered unexpected, for expedited reporting purposes only, when either 
the type of event or the severity of the event is not listed in this protocol, the current 
Investigator’s Brochure, or the Product Label. 
11.3. 
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 (e.g., 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 (e.g., laboratory 
abnormality reported as grade 4 without manifestation of life threatening status), it will be left 
to the investigator’s judgment to also report these abnormalities as SAEs. For any AE that applies 
to this situation, comprehensive documentation of the event’s severity status must be recorded 
in the patient’s medical record.   
11.4. 
Maximum Intensity 
The Investigator will evaluate all AEs and SAEs with regard to maximum intensity and relationship 
to study drug.  Maximum intensity should be assigned using one of the severity grades as outlined 
in the NCI-CTCAE v5.0. If the AE is not specifically listed in CTCAE v5.0, the following grades will 
be used: 
• Grade 1: mild 
• Grade 2: moderate 
• Grade 3: severe 
• Grade 4: life-threatening or disabling 
• Grade 5: death 


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11.5. 
Relatedness to Study Drug 
The Investigator must attempt to determine if an AE or SAE is related to the use of study 
treatment based on clinical experience with known drugs, information contained within an 
Investigator’s Brochure, or events listed in a Product Label.  This relationship should be described 
as follows: 
Unlikely   
The event is clearly due to causes distinct from the use of the study drug, such as a 
documented pre-existing condition, the effect of a concomitant medication, a new 
condition which, based on the pathophysiology of the condition and the 
pharmacology of the study drug, would be unlikely to be related to use of the study 
drug. 
 
Possible  
The event follows a reasonable temporal sequence from administration of the study 
drug and the event follows a known response pattern to the study drug BUT the 
event could have been produced by an intercurrent medical condition which, based 
on the pathophysiology of the condition and the pharmacology of the study drug, 
would be unlikely to be related to the use of the study drug OR the event could be 
the effect of a concomitant medication. 
Probable  The event follows a reasonable temporal sequence from administration of the study 
drug and the event follows a known response pattern to the study drug AND the 
event cannot have been reasonably explained by an intercurrent medical condition 
OR the event cannot be the effect of a concomitant medication. 
Definite    The event follows a reasonable temporal sequence from administration of the study 
drug, the event follows a known response pattern to the study drug and based on 
the known pharmacology of the study drug, the event is clearly related to the effect 
of the study drug. 
Unknown   Based on the evidence available, causality cannot be ascribed. 
Relatedness should be assessed and provided for every AE and assigned to ABI-009, TMZ (± 
radiotherapy), BEV, and/or CCNU as appropriate. If more than one of the study agents may be 
considered as the cause, relatedness is to be reassessed and provided as additional information 
becomes available. 
11.6. 
Adverse Event Reporting 
Adverse events that are serious, unexpected, and at least possibly related to study participation 
will be reported to the Institutional Review Board and to the FDA within the timelines described 
below. All other AEs, such as those that are expected, or are unlikely or definitely not related to 
the study participation, are to be reported per the IRB’s requirements and to FDA as part of 
regular data submission at the time of annual IND report. The Principal Investigator is obligated 
to provide progress and safety summaries to Aadi Bioscience, Inc, the IND-holder of ABI-009, for 
inclusion in its reports to Regulatory Authorities. Aadi Bioscience, Inc. will provide copies of IND 
safety reports in all studies with ABI-009 to the investigators for local reporting to their respective 
IRBs. 


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11.6.1. 
Reporting Procedures for Serious Adverse Events 
Any AE that meets any criterion for an SAE requires the completion of a SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF.  
The Principal Investigator must be notified within 24 hours of learning of any SAE, regardless of 
attribution, occurring during the study or within 30 days of the last administration of the study 
drug.  
Aadi Bioscience, Inc. must be notified 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 FDA must be notified within 7 calendar days of any unexpected fatal or life-threatening AE 
with possible relationship to study drug, and 15 calendar days of any event that is considered: 1) 
serious, 2) unexpected, and 3) at least possibly related to study participation.   
The IRB must be notified within five (5) days of any promptly reportable information (PRI).  The 
following events meet the definition of PRI: 
• New or increased risk. 
• Protocol deviation  
o   that harmed a patient or placed patient at risk of harm, or  
o   made without prior approval to eliminate an immediate hazard to a patient 
• Audit, inspection, inquiry or written report by a federal agency 
• Allegation of noncompliance or finding of noncompliance 
• Breach of confidentiality 
• Unresolved patient complaint 
• Suspension or premature termination by the sponsor, investigator or institution 
• Incarceration of a patient in a research study not approved to involve prisoners 
• Adverse events or IND safety reports that require a change to the protocol or consent 
• Information where the sponsor requires prompt reporting to the IRB. 
The investigator is required to ensure that the data on these forms is accurate and consistent. 
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time of signing of the informed consent form to 28 days after the last dose of IP), and 
those made known to the investigator at any time thereafter that are suspected of being related 
to IP.   
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents. If a patient died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to AADi Drug Safety 
as soon as these become available. Any follow-up data will be detailed in a subsequent SAE 
Report Form, or approved equivalent form, and sent to AADi Drug Safety.  
Where required by local legislation, the investigator is responsible for informing the IRB/EC of 
the SAE and providing them with all relevant initial and follow-up information about the event. 
The investigator must keep copies of all SAE information on file including correspondence with 
AADi and the IRB/EC. 


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11.7. 
Pregnancy and Breast-feeding Reporting 
If a pregnancy occurs in a female patient while the patient is taking protocol-required therapies, 
the patient must discontinue study immediately and the pregnancy must be reported to Aadi 
immediately. The female patient should be advised to see an obstetrician-gynecologist for 
further evaluation and counseling. 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.  
If a pregnancy occurs in a female partner of a male patient taking protocol-required therapies, 
the male should notify the Investigator immediately and the pregnant female partner should be 
advised to call her healthcare provider. 
The investigator will follow the female until completion of the pregnancy and must notify Aadi 
Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form or approved equivalent form. If a lactation 
case occurs while the female patient is taking protocol-required therapies, report the lactation 
case to AADi immediately. 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. 
11.8. 
Data and Safety Review 
Safety monitoring during the study will be the responsibility of the Principal Investigator and will 
occur through frequent teleconferences and/or face-to-face meetings with other study staff.   
Patients enrolled to the trial will be monitored for AEs by the Investigator and clinical co-
investigators. Adverse events will be graded according to the NCI-CTCAE v5.0. Toxicity 
assessments are required prior to study treatment, at the beginning of each treatment cycle, 
following termination of study treatment, and may be performed at any additional time at the 
discretion of the treating physician.  
All AEs will be evaluated for duration, intensity and relationship to (association with) the study 
treatment or other potential causes. All AEs except lab abnormalities will be recorded regardless 
of causality. Adverse events that are: 1) serious, 2) unexpected, and 3) at least possibly related 
to study participation will be reported to the Institutional Review Board within 5 business days 
and to the FDA within 15 calendar days (or 7 calendar days for deaths). All other AEs, such as 
those that are expected, or are unlikely, or definitely not related to the study participation, are 
to be reported annually to the IRB and FDA as part of regular data submission at the time of 
continuing review. 
 


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12. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
12.1. 
Discontinuation from Treatment and the Study 
A patient may be removed from the study for a variety of reasons, including: 
• Progressive disease according to the RANO criteria 
• Initiation of treatment with an alternative anticancer therapy 
• Patient withdraws consent to continue in the trial 
• Patient develops an AE or intercurrent condition that precludes further participation 
or requires a prohibited treatment 
• The investigator withdraws the patient in the patient’s best interest 
• The patient becomes pregnant 
• The patient is lost to follow-up (defined as inability to contact the patient on at least 
2 separate occasions over a period of 4 weeks) 
• Administrative reasons (the patient is unable to return to the site, moves away from 
the investigational site, other social reasons) 
Patients who withdraw in the absence of progressive disease will be followed for progression. 
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 (eg, survival). Every effort 
should be made to collect survival data after patient withdraws from treatment.  
Patients have the right to withdraw from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or at the institution. 
12.2. 
Patient Replacement 
Any patient who is enrolled but does not receive an infusion of ABI-009 will be replaced. 
12.3. 
Investigator or Sponsor Decision to Withdraw or Terminate Patient’s Participation 
Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a patient(s) from 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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13. 
REGULATORY OBLIGATIONS 
13.1. 
Ethical Considerations 
This study will be conducted in accordance with current Regulatory Authorities regulations, ICH 
GCP guidelines, the principles of the Declaration of Helsinki, and local ethical and legal 
requirements. 
13.2. 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the informed 
consent document to be used at his or her site. Updates to the template are to be communicated 
formally in writing from AADi to the investigator. The written informed consent document is to 
be prepared in the language(s) of the potential patient population. 
Before a patient’s participation in the clinical study, the investigator is responsible for obtaining 
written informed consent from the patient after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or the IP is administered.  
The investigator is also responsible for asking the patient if the patient has a primary care 
physician and if the patient agrees to have his/her primary care physician informed of the 
patient’s participation in the clinical study. If the patient agrees to such notification, the 
investigator is to inform the patient’s primary care physician of the patient’s participation in the 
clinical study. If the patient does not have a primary care physician and the investigator will be 
acting in that capacity, the investigator is to document such in the patient’s medical record. 
The acquisition of informed consent and the patient’s agreement or refusal of his/her notification 
of the primary care physician is to be documented in the patient’s medical records, and the 
informed consent form to be signed and personally dated by the patient or a legally acceptable 
representative and by the person who conducted the informed consent discussion. The original 
signed informed consent form is to be retained in accordance with institutional policy, and a copy 
of the signed consent form is to be provided to the patient or legally acceptable representative. 
If a potential patient is illiterate or visually impaired and does not have a legally acceptable 
representative, the investigator must provide an impartial witness to read the informed consent 
form to the patient and must allow for questions. Thereafter, both the patient and the witness 
must sign the informed consent form to attest that informed consent was freely given and 
understood.   
13.3. Institutional Review Board (IRB) Approval and Consent  
A copy of the protocol, proposed informed consent form, other written patient information, and 
any proposed advertising material must be submitted to the IRB for written approval. A copy of 
the written approval of the protocol and informed consent form must be received by Aadi before 
recruitment of patients into the study and shipment of Aadi IP. 
The investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document. The 


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investigator is to notify the IRB of deviations from the protocol or SAEs occurring at the site and 
other AE reports received from Aadi, in accordance with local procedures. 
The investigator is responsible for maintaining IRB approval throughout the duration of the study. 
Copies of the investigator’s reports and the IRB continuance of approval must be sent to Aadi. 
13.4. 
Confidentiality 
The investigator must ensure that the patient’s confidentiality is maintained for documents 
submitted to Aadi. 
• Patients are to be identified by a unique patient identification number. 
• Where permitted, date of birth is to be documented and formatted in accordance 
with local laws and regulations. 
• On the CRF demographics page, in addition to the unique patient identification 
number, include the age at time of enrollment. 
• For SAEs reported to Aadi, patients are to be identified by their unique patient 
identification number, initials (for faxed reports, in accordance with local laws and 
regulations), and date of birth (in accordance with local laws and regulations). 
• Documents that are not submitted to Aadi (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the investigator 
and institution permit authorized representatives of the company, of the regulatory agency(s), 
and the IRB direct access to review the patient’s original medical records for verification of study-
related procedures and data. Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study. The 
investigator is obligated to inform and obtain the consent of the patient to permit such 
individuals to have access to his/her study-related records, including personal information. 
13.5. 
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. 
13.6. 
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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14. 
DATA HANDLING AND RECORDKEEPING 
14.1. 
Patient Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), patients 
who have provided written informed consent must also sign a patient authorization to release 
medical information to the study Sponsor and allow a regulatory authority, or Institutional 
Review Board access to patient’s medical information relevant to the study. 
14.2. 
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. 
14.3. 
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. 
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for at least 
two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
14.4. 
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 
(Section 5), the investigator can search publicly available records (where permitted) to ascertain 
survival status.  
This ensures that the data set(s) produced as an outcome of the study is/are as comprehensive 
as possible. 
14.5. 
The investigator is responsible Sample Storage and Destruction 
Any blood or tumor sample collected according to the Schedule of Assessments (Section 5) 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 


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valid data throughout the course of the study. This can also include, but is not limited to, 
investigation of unexpected results, incurred sample reanalysis, and analyses for method transfer 
and comparability.  
All samples and associated results will be no less than single coded prior to being shipped from 
the site for analysis, or storage. Tracking of samples will be independent of the patient’s 
identification number for the study. Results are stored in a secure database to ensure 
confidentiality.   
Results from this analysis are to be documented and maintained, but are not necessarily reported 
as part of this study.  
The records should be retained by the investigator/sponsor according to ICH, local regulations, 
or as specified in the Clinical Trial Agreement, whichever is longer; but at a minimum, all study 
documentation must be retained for 2 years after the last marketing application approval in an 
ICH region or after at least 2 years have elapsed since formal discontinuation of clinical 
development of ABI-009. 
Since the evaluations are not expected to benefit the patient directly or to alter the treatment 
course, the results of other exploratory studies are not placed in the patient’s medical record and 
are not to be made available to the patient, members of the family, the personal physician, or 
other third parties, except as specified in the informed consent. 
The patient retains the right to request that the sample material be destroyed by contacting the 
Investigator.  Following the request from the patient, the investigator is to provide the sponsor 
with the required study and patient number so that any remaining blood or tumor samples and 
any other components from the cells can be located and destroyed. Samples will be destroyed 
once all protocol-defined procedures are completed.   
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from the 
sample materials and is responsible for the destruction of the sample(s) at the request of the 
patient through the Investigator, at the end of the storage period, or as appropriate (e.g., the 
scientific rationale for experimentation with a certain sample type no longer justifies keeping the 
sample). If a commercial product is developed from this research project, the sponsor owns the 
commercial product. The patient has no commercial rights to such product and has no 
commercial rights to the data, information, discoveries, or derivative materials gained or 
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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1. 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. 
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
The Principal Investigator is responsible for assuring that all the required data will be collected 
and entered onto the case report forms. Periodically, monitoring visits will be conducted and the 
Principal Investigator will provide access to his/her original records to permit verification of 
proper entry of data.  At the completion of the study, all case report forms will be reviewed by 
the Principal Investigator and will require his/her final signature to verify the accuracy of the data. 
The Principal Investigational is responsible for Study Drug Accountability. Study drug ABI-009 for 
this study will be provided by Aadi Bioscience, Inc.  The recipient will acknowledge receipt of the 
drug indicating shipment content and condition.  Damaged supplies will be replaced.  Accurate 
records of all study drug dispensed from and returned to the study site are to be maintained.  
The study site will not destroy or dispose of unopened vials of ABI-009, without written direction 
from Aadi Bioscience, Inc.   
15.2. 
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. 
15.3. 
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 


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evaluate the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 


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


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17. 
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Appendix 1. Karnofsky Performance Status 
 
Able to carry on normal activity and 
to work; no special care needed. 
  100   
Normal no complaints; no evidence of 
disease 
90 
Able to carry on normal activity; minor signs 
or symptoms of disease 
80 
Normal activity with effort; some signs or 
symptoms of disease 
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance 
needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs 
50 
Requires considerable assistance and 
frequent medical care 
Unable to care for self; requires 
equivalent of institutional or hospital 
care; disease may be progressing 
rapidly. 
40 
Disabled; requires special care and 
assistance 
30 
Severely disabled; hospital admission is 
indicated although death not imminent 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary 
10 
Moribund; fatal processes progressing 
rapidly 
0 
Dead 
 
 


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Appendix 2. Response Assessment for Neuro-Oncology (RANO) 
Response and progression of tumors in the brain will be evaluated using the Response 
Assessment in Neuro-Oncology (RANO) Working Group criteria, which, in addition to 
radiographic scans, comprise elements of the neurological exam, KPS and steroid use. Response 
assessments are derived from baseline assessments (prior to study treatment) or Best Response. 
Evaluable for Objective Response   Only those patients who have measurable disease at baseline, 
have received at least one cycle of therapy and have had their disease re-evaluated will be 
considered evaluable for response.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior 
to the end of Cycle 1 also will be considered evaluable.) 
Measurable Disease 
Bidimensionally measurable lesions with clearly defined margins by 
MRI or CT scan, with two perpendicular diameters of at least 10 
mm, visible on two or more axial slices that are preferably, at most, 
5 mm apart with 0-mm skip. 
Non-Measureable Disease 
Either unidimensionally measurable lesions, masses with margins 
not clearly defined, or lesions with maximal diameters less than 10 
mm. 
Number of Lesions 
If there are multiple lesions, a minimum of the two largest lesions 
should be measured and the sum of the products of the 
perpendicular diameters of these lesions should be determined.  
However, given the heterogeneity of high-grade gliomas and the 
difficulty in measuring some lesions, a maximum of five of the 
largest lesions may be measured. 
Objective Status for High Grade Gliomas 
Unless progression is observed, objective status can only be determined when all measurable 
and non-measurable lesions are assessed using the same techniques as at baseline. 
Complete Response (CR)   
Requires all of the following:  
• Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks;   
• No new lesions;   
• Stable or improved non-enhancing (T2/FLAIR) lesions;  
• Patient must be off corticosteroids (or on physiologic replacement doses only); and  
• Patient is stable or improved clinically. 
Partial Response (PR) 
Requires all of the following:  
• Greater than or equal to 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained 


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for at least 4 weeks;   
• No progression of non-measurable disease; 
• No new lesions; 
• Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan.  The corticosteroid dose at the time 
of the scan should be no greater than the dose at time of baseline scan; and 
• Patient is stable or improved clinically. 
Stable Disease (SD) 
Requires all of the following:  
• Does not qualify for CR, PR or progression; and 
• Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan.  In the event that the corticosteroid dose was 
increased for new symptoms and signs without confirmation of disease progression 
on neuro-imaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan 
considered to show stable disease will be the scan obtained when the corticosteroid 
dose was equivalent to the baseline dose. 
Progression (PD) 
Defined by any of the following:  
• Greater than or equal to a 25% increase in the sum of products of perpendicular 
diameters of enhancing lesions compared with the smallest tumor measurement 
obtained either at baseline (if no decrease) or best response, on stable or increasing 
doses of corticosteroids; or  
• Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses 
of corticosteroids compared with baseline scan or best response after initiation of 
therapy not caused by comorbid events; or  
• Appearance of any new lesion; or  
• Clear clinical deterioration not attributable to other causes apart from the tumor or 
changes in corticosteroid dose; or  
• Failure to return for evaluation as a result of death or deteriorating condition, or 
clear progression of non-measurable disease. 
Best Overall Response 
Best response will be calculated from the sequence of objective status.  
For patients who are having all disease sites assessed at every evaluation period, the best 
response will be defined as the best objective status.  If the response does not persist at the next 
routinely-scheduled scan, the response will still be recorded based on the prior scan but will be 
designated as a non-sustained response.  If the response is sustained, e.g. still present on the 
subsequent scan, it will be recorded as a sustained response, lasting until the time of tumor 
progression.  Best response is unknown if the patient does not qualify for a best response or 
increasing disease and if all objective status determinations before progression are unknown.