Clinical trial NCT04461600
Conditions: Triple Negative Breast Cancer
Keywords: TNBC, Notch activated
Sponsor: Ayala Pharmaceuticals, Inc,
Start date: 2020-08-14; Completion date: 2022-10-11
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The current study is designed to evaluate the efficacy and safety of AL101 monotherapy in subjects with Notch-activated recurrent or metastatic TNBC; Notch activation will be determined by a Next Generation Sequencing (NGS) test.

Detailed description:

Arms: arm 1: The study included a lead-in cohort with 6 subjects at 6mg AL101 weekly. 13 additional patients were treated with 4mg AL101 weekly.
Interventions: intervention 1: AL101
Intervention descriptions: intervention 1: AL101 is an inhibitor of gamma secretase-mediated Notch signaling.

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL
Protocol Title: 
TENACITY: A Phase 2, Multicenter, Open-label, Single-arm Study 
of AL101 Monotherapy in Patients with Notch-activated Triple 
Negative Breast Cancer
Protocol Number: 
AL-TNBC-01
Investigational 
product: 
AL101
Study Indications
Notch Activated Recurrent or Metastatic Triple Negative Breast 
Cancer
Study Phase: 
2
Sponsor Name:
Ayala Pharmaceuticals, Inc.
Legal Registered 
Address:
at c/o MWE Corporate Services, 1007 N. Orange St., 4th Floor, 
Wilmington, DE 19801
Regulatory Agency 
Identifier No(s):
IND: 147711
Sponsor Contact:
Gary Gordon, MD, PhD
Chief Medical Officer
gary.g@ayalapharma.com  
Approval Date:
12 August 2020
CONFIDENTIALITY STATEMENT
Information in this protocol is confidential and may not be disclosed to parties other than study personnel 
and the Ethics Committee/Institutional Review Board directly involved in this study. It should be kept 
secure and its contents should not be disclosed to any third party without the prior written consent of Ayala 
Pharmaceuticals, Inc.
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Protocol Title
TENACITY: A Phase 2, Multicenter, Open-label, Single-arm Study 
of AL101 Monotherapy in Patients with Notch-activated Triple 
Negative Breast Cancer
Protocol Number
AL-TNBC-01
Version and Date
Version 3.0, 12 August 2020
Amendment No. 
Amendment 2
Regulatory Agency 
Identifier No(s):
IND: 147711
Principal Investigator
I have received and read the protocol. I, the Principal Investigator of the study, approve of, and will 
comply with all conditions, instructions and restrictions described in this protocol. I am aware that my 
adherence to the above protocol is mandatory and that any changes in the protocol or consent form, 
except those necessary to eliminate apparent immediate hazards to human subjects, must first be approved 
in writing by Ayala Pharmaceuticals, Inc. and the respective Ethics Committee/Institutional Review 
Board. By my signature, I agree to personally supervise the conduct of this study in compliance with the 
Declaration of Helsinki, International Council for Harmonisation of Good Clinical Practice (ICH-GCP) 
Guidelines, instructions from Ayala Pharmaceuticals, Inc. representatives, and the applicable parts of the 
United States Code of Federal Regulations or local regulations governing the conduct of clinical studies. 
Failure to adhere to these stipulations may constitute a breach of federal regulations and may result in 
termination of the study.
Investigator Signature
Date
Name
Institution,
City, State,  Country
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CURRENT PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Date
Protocol V3.0, Amendment 2
12 August 2020
Protocol V2.0, Amendment 1
06 April 2020
Protocol V1.0, original
02 March 2020
Amendment 2 (V3.0); 12 August 2020
Section
Summary of Change
Rationale for Change
1.1 Synopsis
1.3 Schedule of Activities
4.1 Study design
8.4.4 Sample collection
Clarify that on-treatment biopsy 
will be collected (instead of at 
progression)
Clarify that blood samples for 
pharmacokinetics and 
biomarkers will be collected on 
the same day as on-treatment 
biopsy collection.
To ensure biopsies are collected on 
treatment and increase compliance to 
the protocol 
To allow correlative evaluations with 
the on-treatment biopsy assessment
1.2 Study schema
Update to align with Table 8 in 
the statistical section
For consistency within the protocol
1.3 Schedule of Activities
8.1.1 RECIST, Table 5
Delete reference to ‘Early 
Discontinuation’
In this study end of study and early 
discontinuation are synonymous 
2.3.1 Risk assessment
Clarify mitigation strategy for 
anaphylaxis 
For clarity and alignment across 
protocol sections
5.2 Exclusion criteria
Update exclusion criterion 11f 
(creatinine)
Allow inclusion based on normal 
creatinine values, as well as sufficient 
GFR, as AL101 is not expected to 
impact renal function
6.4 AL101 Dose 
modification and toxicity 
management guidelines 
(Table 3)
6.4.4 Guidelines of the 
management of colitis 
(Table 4)
Introduce change in regimen (2 
weeks on / 1 week of) for first 
episode of Grade 2 or 3 diarrhea 
and Grade 2 Colitis before dose 
reduction on subsequent 
episodes
To allow investigators to use a 2 weeks 
on 1 weeks off regime at 6 mg QW, 
before implementing dose reduction.  
The aim is  to introduce a scheduled 
dose interruption to prevent recurrence 
of toxicity
6.4 AL101 Dose 
modification and toxicity 
management guidelines 
(Table 3)
10.2, Appendix 2 Clinical 
laboratories
Add lipase for subjects 
experiencing ≥Grade 2 diarrhea 
adverse events
Per request of the Spanish competent 
authority
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Section
Summary of Change
Rationale for Change
6.4.1 Treatment of 
infusion reactions
8.3.5 Adverse events of 
special interest
10.3.2 Definition of SAE
Emphasize that Grade 3 or 4 
infusion reactions should be 
reported as SAE.
Clarify that all infusion 
reactions must be reported as 
adverse events of special 
interest.
To ensure sites are aware of these 
reporting requirements
7.2 Discontinuation of 
investigational product
Clarify that subjects being 
managed with dose interruption 
for toxicity should have their 
study assessments followed per 
SoA.
For continued care and safety of 
subject during the dose interruption
9 Statistical 
considerations 
Clarify the 4 responses in Stage 
1 will trigger Stage 2
Clarify efficacy evaluable 
analysis population
For consistency and clarity
General
Correct typos, hyperlinks, style 
and formatting
Align across protocol sections
For consistency and clarity
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TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL ..................................................................................................1
APPROVALS ..................................................................................................................................2
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ...................................................................3
CURRENT PROTOCOL AMENDMENT SUMMARY OF CHANGES......................................4
1.
PROTOCOL SUMMARY..........................................................................................11
1.1.
Synopsis......................................................................................................................11
1.2.
Study Schema .............................................................................................................15
1.3.
Schedule of Activities (SoA)......................................................................................16
2.
INTRODUCTION......................................................................................................21
2.1.
Study Rationale...........................................................................................................21
2.2.
Background.................................................................................................................21
2.3.
Benefit/Risk Assessment ............................................................................................22
2.3.1.
Risk Assessment.........................................................................................................22
2.3.2.
Benefit Assessment.....................................................................................................23
2.3.3.
Overall Benefit Risk Conclusion................................................................................23
3.
OBJECTIVES AND ENDPOINTS............................................................................24
4.
OVERALL STUDY DESIGN....................................................................................26
4.1.
Study Design...............................................................................................................26
4.2.
Scientific Rationale for Study Design ........................................................................27
4.2.1.
Rationale for Study Population...................................................................................27
4.3.
Justification for Dose..................................................................................................28
4.4.
Study Duration............................................................................................................29
4.5.
End of Study Definition..............................................................................................29
5.
ELIGIBILITY CRITERIA .........................................................................................30
5.1.
Inclusion Criteria ........................................................................................................30
5.2.
Exclusion Criteria.......................................................................................................31
5.3.
Lifestyle Consideration...............................................................................................33
5.3.1.
Dietary and Other Restrictions ...................................................................................33
5.4.
Subject Identification..................................................................................................33
5.5.
Screen Failures............................................................................................................33
6.
INVESTIGATIONAL PRODUCT AND CONCOMITANT THERAPY.................34
6.1.
Investigational Product Administered ........................................................................34
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6.2.
Handling, Storage and Accountability........................................................................35
6.3.
Compliance of Investigational Product ......................................................................35
6.4.
AL101 Dose Modification and Toxicity Management Guidelines ............................35
6.4.1.
Treatment of Infusion Reactions ................................................................................44
6.4.2.
Guidelines for Management of Diarrhea ....................................................................45
6.4.3.
Guidelines for the Management of Hepatotoxicity ....................................................46
6.4.3.1.
Potential Drug-Induced Liver Injury (DILI) / Hy’s Law............................................46
6.4.4.
Guidelines for the Management of Colitis..................................................................48
6.5.
Treatment of Overdose ...............................................................................................49
6.6.
Concomitant Therapy .................................................................................................49
6.6.1.
Premedication to Prevent Hypersensitivity Reaction .................................................49
6.6.2.
Premedication with Corticosteroids............................................................................50
6.6.3.
Allowed Medications..................................................................................................50
6.6.4.
Prohibited Concomitant Medication...........................................................................51
6.7.
Intervention after the End of the Study.......................................................................52
7.
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND/OR 
STUDY.......................................................................................................................53
7.1.
Stopping Rules............................................................................................................53
7.2.
Discontinuation of Investigational Product ................................................................53
7.3.
Withdrawal from the Study ........................................................................................54
7.4.
Lost to Follow-up .......................................................................................................54
8.
STUDY ASSESSMENTS AND PROCEDURES......................................................56
8.1.
Efficacy Assessments .................................................................................................56
8.1.1.
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.................................56
8.1.2.
Patient Reported Outcome: European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire 30 questions (EORTC 
QLQ-C30) and Breast Cancer 45 Questions (EORTC QLQ-BR45)..........................58
8.2.
Safety Assessments.....................................................................................................58
8.2.1.
Medical History and Prior Therapies..........................................................................58
8.2.2.
Eastern Cooperative Oncology Group (ECOG) Performance Status.........................58
8.2.3.
Physical Examination .................................................................................................59
8.2.4.
Vital Signs ..................................................................................................................59
8.2.5.
Electrocardiogram.......................................................................................................59
8.2.6.
Clinical Safety Laboratory Assessments ....................................................................59
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8.3.
Adverse Events and Serious Adverse Events.............................................................60
8.3.1.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information............................................................................................60
8.3.2.
Method of Detecting AEs and SAEs ..........................................................................61
8.3.3.
Follow-up of AEs and SAEs.......................................................................................61
8.3.4.
Regulatory Reporting Requirements for SAEs...........................................................62
8.3.5.
Adverse Events of Special Interest.............................................................................62
8.3.5.1.
Colitis..........................................................................................................................62
8.3.5.2.
Infusion Reactions (including Anaphylaxis) ..............................................................63
8.3.5.3.
Keratoacanthoma........................................................................................................63
8.3.5.4.
Hepatic Function Abnormalities (hepatotoxicity) ......................................................63
8.3.6.
Disease Progression....................................................................................................63
8.3.7.
Death Events...............................................................................................................64
8.3.8.
Pregnancy ...................................................................................................................64
8.4.
Biomarkers and Pharmacokinetics .............................................................................64
8.4.1.
Activating Notch Alteration Detection by NGS Assay..............................................64
8.4.2.
Pharmacokinetics........................................................................................................64
8.4.3.
Other Biomarkers........................................................................................................65
8.4.4.
Sample Collection.......................................................................................................65
8.5.
Genetics ......................................................................................................................65
8.6.
Unscheduled Visits.....................................................................................................65
9.
STATISTICAL CONSIDERATIONS .......................................................................67
9.1.
Statistical Hypothesis and Sample Size Determination..............................................67
9.2.
Analysis Populations ..................................................................................................67
9.3.
Statistical Analyses.....................................................................................................68
9.3.1.
Subject Disposition.....................................................................................................68
9.3.2.
Demographic and Baseline Characteristics ................................................................69
9.3.3.
Efficacy.......................................................................................................................69
9.3.3.1.
Definitions of Efficacy Endpoints ..............................................................................69
9.3.3.2.
Analysis of Efficacy Endpoints ..................................................................................69
9.3.4.
Safety and Tolerability Analysis ................................................................................69
9.4.
Interim Analyses.........................................................................................................70
9.5.
Data Monitoring Committee (DMC)..........................................................................70
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..................................................................................................71
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................71
10.1.1.
Ethical Aspects ...........................................................................................................71
10.1.1.1.
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) and 
Regulatory Authorities................................................................................................71
10.1.1.2.
Declaration of Helsinki/Good Clinical Practice .........................................................71
10.1.1.3.
Subject Information and Informed Consent ...............................................................72
10.1.1.4.
Personal Data Protection.............................................................................................72
10.1.1.5.
Audits and Inspections................................................................................................73
10.1.1.6.
Data Quality Assurance..............................................................................................73
10.1.2.
Study Monitoring........................................................................................................74
10.1.3.
Study Documentation .................................................................................................74
10.1.3.1.
Change in Protocol .....................................................................................................75
10.1.3.2.
Site Initiation Visit/Investigator Meeting...................................................................75
10.1.3.3.
Source Document........................................................................................................75
10.1.3.4.
Recording of Data on Electronic Case Report Form (eCRF).....................................75
10.1.3.5.
Investigator Site File...................................................................................................76
10.1.3.6.
Clinical Study Supplies...............................................................................................76
10.1.4.
Data Management.......................................................................................................76
10.1.5.
Study Completion.......................................................................................................77
10.1.6.
Clinical Study Report .................................................................................................77
10.1.7.
Disclosure ...................................................................................................................77
10.1.8.
Records .......................................................................................................................77
10.1.9.
Financing and Insurance.............................................................................................78
10.2.
Appendix 2: Clinical Laboratory Tests.......................................................................79
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting........................................................................80
10.3.1.
Definition of AE .........................................................................................................80
10.3.2.
Definition of SAE.......................................................................................................81
10.3.3.
Definition of Suspected and Unsuspected Adverse Reaction.....................................82
10.3.4.
Recording and Follow-up of AEs and SAEs..............................................................82
10.3.5.
Reporting of SAEs and SUSAR .................................................................................84
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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................86
10.5.
Appendix 5: Medication Guidance.............................................................................89
10.6.
Appendix 6: Summary of Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1............................................................................................................91
10.7.
Appendix 7: Patient Reported Outcomes ...................................................................95
10.8.
Appendix 8: Abbreviations.......................................................................................100
10.9.
Appendix 9: Protocol Amendment History..............................................................103
11.
REFERENCES .........................................................................................................105
LIST OF TABLES
Table 1
Schedule of Activities.................................................................................................16
Table 2
Investigational product ...............................................................................................34
Table 3
Dose Modification Criteria for AL101.......................................................................37
Table 4
Colitis Management....................................................................................................48
Table 5
Imaging Guidelines.....................................................................................................57
Table 6
ECOG Performance Status .........................................................................................59
Table 7
Adverse Event Reporting Timelines to the Sponsor...................................................61
Table 8
Sample Size Hypothesis .............................................................................................67
Table 9
Protocol-Required Safety Laboratory Assessments ...................................................79
LIST OF FIGURES
Figure 1
Study Schema based on Simon’s Two-Stage Optimal Design for Targeted 
Therapy.......................................................................................................................15
Figure 2
Algorithm for p-DILI identification and mandatory SAE reporting in 
subjects with - (i) normal baseline liver biochemistry, and (ii) abnormal 
baseline liver biochemistry.........................................................................................47
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title
TENACITY: A Phase 2, Multicenter, Open-label, Single-arm Study of AL101 Monotherapy in 
Patients with Notch-activated Triple Negative Breast Cancer
Study Rationale and Hypothesis
AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling that is 
currently under development as an antitumor/antiangiogenic agent as monotherapy for the 
treatment of various cancers. A large body of experimental evidence supports the causal role of 
Notch pathway deregulation in cancer development and progression  (Previs, 2015; Wang, 
2015b; Braune, 2016; Vinson, 2016; Xiao, 2016; Zhao, 2017).
Triple negative breast cancer (TNBC) is a heterogeneous disease entity constituting about 15% 
of newly diagnosed breast cancer (BC) cases and a higher percentage of metastatic BC cases 
worldwide. TNBC is associated with poor prognosis and lack of sustained response to 
conventional chemotherapeutic agents (Rouzier, 2005; Dua, 2017; Polk, 2017). Patients with 
recurrent and/or metastatic TNBC have a median survival of approximately 13-24 months 
(Kassam, 2009; Steponaviciene, 2011); therefore, there is an urgent need to identify new 
therapeutic strategies for these patients.
The Notch pathway is activated during mammary gland development and has been implicated as 
a key driver in BC (Collu, 2007). The frequency of Notch mutations or gene rearrangement was 
reported at 5 to 16% in small cohorts of TNBC tumors and high level of Notch expression was 
associated with poorer overall survival (Robinson, 2011; Stoeck, 2014; Wang, 2015a). In 
addition, elevated Hes4 expression, a marker of Notch activation, is associated with poorer 
prognosis in TNBC (Stoeck, 2014).
In nonclinical models, AL101 has a broad-spectrum antitumor activity against solid tumor 
xenografts of diverse histological types at tolerable doses, including breast carcinoma. AL101 
exerted its antitumor activity through direct inhibition of cell proliferation and indirectly via 
inhibition of tumor angiogenesis. In TNBC patient-derived xenograft (PDX) tumor models, the 
presence of activating Notch mutations/fusions correlated with potent response to AL101 
monotherapy.
The current study is designed to evaluate the efficacy and safety of AL101 monotherapy in 
subjects with Notch-activated recurrent or metastatic TNBC; Notch activation will be determined 
by a Next Generation Sequencing (NGS) test.
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Objectives and Endpoints (Primary and Secondary only)
Objectives
Endpoints
Primary

To evaluate the efficacy of AL101 
monotherapy in subjects with 
Notch-activated recurrent or metastatic 
TNBC

Proportion of subjects who demonstrate an 
overall response rate (ORR) defined as 
partial response (PR) + complete response 
(CR) as assessed by investigator based on 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1
Secondary

Efficacy - Secondary

Clinical benefit response rate (CBR) 
defined as CR + PR + stable disease (SD) 
by investigator review based on 
RECIST v1.1

Duration of response (DOR) by 
investigator review based on RECIST v1.1

Progression free survival (PFS)

Proportion of subjects who have PFS at 6 
months

Overall survival (OS)

Quality of life (QoL) as determined by 
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire 30 questions (EORTC 
QLQ-C30) and Breast Cancer 45 questions 
(EORTC QLQ-BR45)

To evaluate the safety and tolerability of 
AL101 monotherapy in subjects with 
recurrent or metastatic TNBC

Frequency, duration and severity of 
treatment-emergent adverse events 
(TEAEs) and serious adverse events 
(SAEs)

Incidence of clinically significant 
abnormalities in laboratory parameters, 
electrocardiograms (ECGs), vital signs and 
physical examination
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Overall Design
This is an open-label, multicenter, Phase 2, Simon two-stage optimal design for targeted therapy 
study of single arm AL101 monotherapy in subjects with Notch-activated recurrent or metastatic 
TNBC whose disease has recurred or progressed after 3 or fewer lines of prior therapy.
The design will include a lead-in cohort with 6 subjects to ascertain safety of the investigational 
product (IP), AL101, 6 mg weekly (QW). The safety will be reviewed on a regular schedule 
(weekly calls with investigators, and quarterly reviews with the Data Monitoring Committee 
[DMC]). After the 6th subject is enrolled and completes 4 weeks of therapy (1 cycle), the results 
will be reviewed in aggregate and, if the safety is acceptable (as defined below), the study will 
continue at 6 mg administered QW. Note, if safety is not acceptable amongst the first 6 subjects 
dosed at 6 mg QW, the IP dose will be reduced to 4 mg QW. The decision on which dose to use 
for the remainder of the study will be determined after a formal safety assessment with the 
investigators and the DMC.
Acceptable safety:
-
2 or fewer subjects experience Grade 3 or 4 diarrhea lasting more than 3 days
-
2 or fewer subjects experience another specific Grade 3 or 4 adverse event (AE) which is 
attributable to IP
After the lead-in phase with AL101 6 mg QW, the study will proceed to complete the described 
Simon two-stage design as shown in Figure 1 and described in Section 9.1.
Prior to entering the study, to determine eligibility, potential candidates who sign a separate 
pre-screening informed consent, will undergo pre-screening assessment for evaluation of Notch 
mutational status from a persistent locally advanced or metastatic lesion.
After signing an informed consent, all subjects will then undergo screening assessments to 
determine study eligibility over a 28-day Screening period, including TNBC molecular 
characterization. Eligibility criteria for study entry will be assessed locally by the investigator; 
radiographic scans at screening and from the prior 12 months will be collected and held for 
possible future retrospective independent evaluation.
Starting on Cycle 1, Day 1, eligible subjects will be treated with IP intravenously (IV) QW, on 
Days 1, 8, 15 and 22 of each 28-day cycle. Treatment will continue until the occurrence of 
unequivocal radiographic disease progression per RECIST v1.1 as assessed by the investigator, 
or clear clinical progression as assessed by the investigator, or unacceptable toxicity, or other 
reasons for discontinuation.
All subjects will receive premedication with H1- and H2-blockers (refer to Section 6.6.1) and 
corticosteroids as prophylaxis (refer to Section 6.6.2). Toxicity post-AL101 administration will 
be managed as specified in Section 6.4.
During the treatment period, subjects will undergo radiographic assessments every 8 weeks 
(±3 days) for review by the investigator. Radiographic scans will also be collected and held for 
possible future retrospective independent evaluation. Other assessments will be done as specified 
in the Schedule of Activities (Table 1). A repeat of tumor imaging will be required for the 
purposes of confirmation of response (i.e., partial response, and/or complete response). The 
confirmation scan should be no earlier than 4 weeks following the first indication of response.
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Samples from tumor biopsies will be collected at screening from a locally advanced or metastatic 
lesion (fresh or archival within 2 years), and at Cycle 4 Day 1 ±28 days (provided that biopsy 
collection is medically safe and not contraindicated). If an archival tumor block or 25 unstained 
slides are not available, the subject will be required to have a fresh tumor sample obtained at 
screening. Biopsy samples will be evaluated by NGS for genomics, immunohistochemistry 
(IHC) for Notch intracellular domain (NICD) stain, and other biomarkers potentially related to 
sensitivity to AL101 or TNBC prognosis. Blood samples for pharmacokinetics (PK) and 
biomarker analysis will also be collected on the same day as the on-treatment biopsy.
All subjects will undergo end of study (EOS) visit 30 days post last treatment with IP and will be 
contacted to determine survival status at timepoints specified in study duration. In subjects who 
discontinued IP due to toxicity, radiographic imaging will be done every 3 months until disease 
progression or until the subject initiates another anti-cancer therapy.
Disclosure Statement
This is a single group treatment study with no masking.
Number of Subjects
Using the Simon two-stage optimal design (targeting a response of 23% or greater), up to 67 to 
73 subjects will be enrolled, depending on IP dose evaluated in Stage 1 and Stage 2 as follows:

if the AL101 dose is 6 mg QW throughout the study, there will be up to 67 subjects 
evaluated, including the 6 subjects in the lead-in cohort for the Stage 1 evaluation.

if AL101 4 mg is evaluated in Stage 1 and Stage 2, there will up to 73 enrolled subjects 
consisting of up to 67 subjects at AL101 4 mg and 6 subjects in the lead-in cohort of 
AL101 6 mg. Note, the lead-in cohort will not be included in the Stage 1 evaluation.
In both scenarios there will be up to 26 evaluable subjects in Stage 1, and 41 additional evaluable 
subjects in Stage 2  provided at least 4 subjects (out of 26) responded in Stage 1 (Table 8).
Intervention Group
Lead-in phase: AL101 6 mg IV administered QW, on Days 1, 8, 15 and 22 of each 28-day cycle
Main Study: AL101 4 or 6 mg IV administered QW, on Days 1, 8, 15 and 22 of each 28-day 
cycle
Study Duration for Each Subject
For each subject, the study is expected to last as follows:
Screening period: 
Up to 28 days 
Treatment period: 
Until disease progression, unacceptable toxicity, or consent withdrawal
EOS: 
30 days after the last administration of IP 
Long term follow-up: 
Every 3 months for the first year after EOS, then every 6 months for 
the next 2 years and then annually.
Data Monitoring Committee: Yes
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1.2.
Study Schema
Figure 1
Study Schema based on Simon’s Two-Stage Optimal Design for Targeted Therapy
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1.3.
Schedule of Activities (SoA)
Table 1
Schedule of Activities
Treatment Perioda  (by cycles and days of cycle)
1 cycle = 28 days (4 weeks)
Assessments
Pre-
Screena
Screening 
Period 
(days)
Cycle 1
Cycle 2
Cycles 3+
End of Study 
(EOS) Visit 
Long-
Term 
Follow-
upo
-28 to -1
D1
D8 D15 D22
D1
D8 D15 D22
D1
D8 D15 D22
30 days post 
last 
investigational 
product
Prescreen informed consent
X
Informed consent
X
NGS Assay
Xb
Tumor biopsyc
X
Cycle 4 
(±28 days) 
only
Medical & breast cancer 
disease history (including 
therapy and prior scans)
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete physical examd
X
X
X every 
odd cycle 
or as 
clinically 
indicated
X
Symptoms directed PE
X
X
X
X
X
X
X
X every 
even cycle
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CBC w/diff, plateletse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistryf
X
Xg
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
X
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Treatment Perioda  (by cycles and days of cycle)
1 cycle = 28 days (4 weeks)
Assessments
Pre-
Screena
Screening 
Period 
(days)
Cycle 1
Cycle 2
Cycles 3+
End of Study 
(EOS) Visit 
Long-
Term 
Follow-
upo
-28 to -1
D1
D8 D15 D22
D1
D8 D15 D22
D1
D8 D15 D22
30 days post 
last 
investigational 
product
Lipid panelq
X
X
X
Thyroid function (TSH, 
T3, T4)
X
X (every 
12 weeks)
HbA1c
X
X (every 
12 weeks)
HIV, Hepatitis B and C by 
history
X
Coagulation factors
X
X
Xi (every 8 
weeks)
Urinalysisj
X
X
Pregnancy testk
X
X
X
X
X
12 lead ECGl
X
X (every 
12 weeks)
X
AL101 infusion
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
=====================X=====================
X
Radiological imaging and 
Disease evaluation by 
RECIST v1.1m
X
X (every 8 
weeks) 
X 
Xm
Brain MRI (preferred) or CT 
(acceptable) with contrast n
X
X (every 
12 weeks) 
for known 
/suspected 
disease
Blood for biomarkers
X
X 
(predose)
X 
(predose) 
X 
(predose, 
every 8 
X
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Treatment Perioda  (by cycles and days of cycle)
1 cycle = 28 days (4 weeks)
Assessments
Pre-
Screena
Screening 
Period 
(days)
Cycle 1
Cycle 2
Cycles 3+
End of Study 
(EOS) Visit 
Long-
Term 
Follow-
upo
-28 to -1
D1
D8 D15 D22
D1
D8 D15 D22
D1
D8 D15 D22
30 days post 
last 
investigational 
product
weeks) & 
Cycle 4 
(with 
biopsy)
Blood for PKp
X
X
X
X 
(predose)
X 
(predose, 
odd 
cycles) & 
Cycle 4 
(with 
biopsy)
Overall survival
 / 
visito
EORTC QLQ-C30 and 
EORTC QLQ-BR45 (before 
infusion)
X
X
X
X 
X
Abbreviations: CBC = Complete blood count; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; EOS = end of study, EORTC QLQ-C30 = European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 questions; EORTC QLQ-BR45 = European Organization for Research and Treatment of Cancer 
Quality of Life Breast Cancer Module Questionnaire 45; questions; HbA1c = glycosylated hemoglobin; HIV = human immunodeficiency virus; IHC = immunohistochemistry; MRI 
= magnetic resonance imaging; NICD = Notch intracellular domain; NGS = Next generation sequencing; PE = physical examination; RECIST = Response Evaluation Criteria in 
Solid Tumors; TSH = thyroid stimulating hormone.
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Notes to Schedule of Activities:
All assessments to be performed pre-infusion unless stated otherwise.
Visit window will be ±2 days during treatment period, except for imaging ±3 days (if AL101 dosing is delayed by up to 7 days, then 
imaging can be similarly delayed); EOS and Long-term follow-up will be ±7 days.
a.
Pre-screening assessments may be done while potential candidates are on other therapy provided that a separate pre-screening 
informed consent form is signed.
b.
For determining eligibility, potential candidates will undergo a pre-screening assessment to determine Notch mutation status, after 
signing the prescreening ICF. Available genotyping results from within the last 2 years from a commercially available or laboratory 
developed test (LDT) NGS assay are acceptable. If acceptable genotyping results are not available, NGS testing will need to be 
conducted during pre-screening using a commercially available NGS assay, LTD or other validated investigational use only (IUO) 
clinical trial assay using tumor biopsy from within the last 2 years. When available, NGS test results will be shared with investigators 
and determination of Notch mutation status and eligibility will be communicated.
c.
Tumor biopsies (a resection, or core needle or punch biopsy with 20 gauge or larger and at least 2 passes) will be collected both at 
screening (fresh or archival within 2 years, from the same biopsy used for pre-screening), and at Cycle 4 Day 1 ±28 days (fresh 
biopsy, provided medically safe and not contraindicated). If a tumor block or 25 unstained slides are not available, the subject will be 
required to have a fresh tumor sample obtained at screening from a readily accessible persistent locally advanced or metastatic lesion.
d.
Complete physical examination at baseline (refer to Section 8.2.3 for body systems to be evaluated) and every odd cycle thereafter or 
as clinically indicated; targeted physical examination at other time points.
e.
Refer to Section 10.2 for list of parameters
f.
Refer to Section 10.2 for list of parameters
g.
Screening laboratory may be used if conducted within 3-7 days of CID1.
h.
Chemistry will be conducted every week for the first 3 cycles and then every 4 weeks, with the exception of liver function tests 
(aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase/bilirubin) which will be done weekly until week 32, and 
then every 2 weeks thereafter
i.
Coagulation factors will be done on Day 1 of every other cycle (e.g., C3D1, C5D1…)
j.
Urinalysis performed at Screening and as clinically indicated. Refer to Section 10.2 for list of parameters
k.
Pre-menopausal female subjects of childbearing potential only. Urine or serum pregnancy tests are acceptable.
l.
In the event of possible abnormal ECG findings, per the discretion of the investigator, additional ECG reads could be added at follow-
up visits. The ECG evaluation will be performed locally; single ECG will be collected pre-dose (within 1 hour of infusion) and post-
d0se (within 1 hour post end of infusion). Clinically significant ECG abnormalities will be recorded on the electronic case report form 
(eCRF).
m. CT or MRI with contrast are acceptable. Refer to Table 5 for imaging requirements during the study.
n.
For known or suspected brain metastases at baseline repeat brain MRI (preferred)/CT (acceptable) with contrast every 12 weeks. 
Conduct brain MRI/CT with contrast when subject has clinical symptoms. Same modality should be used throughout the study.
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o.
During long-term follow up, subjects will be contacted every 3 months for the first years after EOS, then every 6 months for the next 2 
years and then annually
p.
PK blood samples will be collected as follows: 
Cycle / Day
Hours Relative to Dose (Window)
Cycle 1 / Days1, 8, and 22
Pre-dose (within 1 hour before start of dose)
End-infusion (within 10 minutes of infusion end)
Cycle 2,3,5,7/ Day1
Pre-dose (within 1 hour before start of dose)
Cycle 4 / Day 1 ± 28 days
On same day as on-treatment biopsy is collected
q.
Lipid panel will be taken after at least an 8 hour fast and will include: triglycerides, total cholesterol, low-density lipoprotein(LDL), 
and high-density lipoprotein (HDL).
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2.
INTRODUCTION
2.1.
Study Rationale
AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling that is 
currently under development as monotherapy for the treatment of various cancer. A large body 
of experimental evidence supports the causal role of Notch pathway deregulation in cancer 
development and progression (Previs, 2015; Wang, 2015b; Braune, 2016; Vinson, 2016; Xiao, 
2016; Zhao, 2017).
Triple negative breast cancer (TNBC) is a heterogeneous disease entity constituting about 15% 
of newly diagnosed breast cancer (BC) cases and a higher percentage of metastatic BC cases 
worldwide. TNBC is associated with poor prognosis and lack of sustained response to 
conventional chemotherapeutic agents (Rouzier, 2005; Dua, 2017; Polk, 2017). Patients with 
recurrent and/or metastatic TNBC have a median survival of approximately 13-24 months 
(Kassam, 2009; Steponaviciene, 2011); therefore, there is an urgent need to identify new 
therapeutic strategies for these patients.
The Notch pathway is activated during mammary gland development and has been implicated as 
a key driver in BC (Collu, 2007). The frequency of Notch mutations or gene rearrangement was 
reported at 5 to 16% in small cohorts of TNBC tumors and high level of Notch expression was 
associated with poorer overall survival (Robinson, 2011; Stoeck, 2014; Wang, 2015a). In 
addition, elevated Hes4 expression, a marker of Notch activation, is associated with poorer 
prognosis in TNBC (Stoeck, 2014).
In nonclinical models, AL101 has a broad-spectrum antitumor activity against solid tumor 
xenografts of diverse histological types at tolerable doses, including breast carcinoma. AL101 
exerted its antitumor activity through direct inhibition of cell proliferation and indirectly via 
inhibition of tumor angiogenesis. In TNBC patient-derived xenograft (PDX) tumor models, the 
presence of activating Notch mutations/fusions correlated with potent response to AL101 
monotherapy. For additional information on nonclincial studies, refer to the Investigator’s 
Brochure.
The current study is designed to evaluate the efficacy and safety of AL101 monotherapy in 
subjects with Notch-activated recurrent or metastatic TNBC; Notch activation will be determined 
by a Next Generation Sequencing (NGS) test.
2.2.
Background
Breast cancer is the most common cancer diagnosed among US women and is the second leading 
cause of cancer-related deaths (DeSantis, 2017). TNBC represents 1 of the 4 main molecular 
subtypes of invasive BC (Tamimi, 2012; Dieci, 2014) accounting for 10-20% of total cases. It is 
significantly more common in African American premenopausal women and women with a 
breast cancer type 1 susceptibility gene (BRCA1) mutation (Perou, 2011; Lin, 2012). TNBC is 
biologically heterogeneous but can be mainly identified by a negative phenotype for the estrogen 
receptor (ER) and progesterone receptor and a lack of gene amplification/protein overexpression 
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for the human epidermal growth factor receptor 2 (HER2). These biologic characteristics confer 
a higher aggressiveness and relapse risk than that observed in all other BC subtypes (Rouzier, 
2005; Dua, 2017; Polk, 2017).
Due to the loss of the aforementioned tumor cell receptors, patients with TNBC do not benefit 
from hormonal therapy or treatments targeting the oncogenic HER2 pathway (Lin, 2012). The 
standard of care for patients with recurrent and/or metastatic disease is cytotoxic chemotherapy 
(taxane- or anthracycline-containing regimens for TNBC, and platinum-based chemotherapy for 
BRCA1/2 mutation-associated TNBC) (Cardoso, 2017), leading to a median survival of 
approximately 13 months from the time of recurrence or diagnosis of distant metastases 
(Kassam, 2009; Steponaviciene, 2011). A recent meta-analysis of first line treatment in 
metastatic TNBC in phase 3 studies reported pooled objective response rate (ORR) of 23%, 
median overall survival (OS) of 17.5 months, and median progression-free survival (PFS) of 
5.4 months with single-agent chemotherapy (Li, 2019).
Currently, two poly (ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib are 
approved for TNBC patients with BRCA mutations. Atezolizumab in combination with nab-
paclitaxel was recently approved for programmed death-ligand 1 (PD-L1) - positive locally 
advanced or metastatic TNBC (Li, 2019; Narayan, 2020).
The Notch signaling pathway has emerged as a potential pathway in the pathogenesis and tumor 
progression of TNBC. Notch receptors are associated with the regulation of tumor-initiating cells 
(TICs) behavior, as well as with the etiology of TNBC. There is a strong evidence that the Notch 
pathway is a relevant player in mammary cancer stem cells maintenance and expansion. In 
addition, Notch receptors expression and activation strongly correlate with the aggressive 
clinicopathological and biological phenotypes of BC (e.g., invasiveness and chemoresistance), 
which are relevant characteristics of TNBC subtype (Giuli, 2019).
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of AL101 may be found in the Investigator’s Brochure (IB).
2.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Investigational Product AL101
Hepatic function 
abnormalities and drug-
induced liver injury (DILI)
Refer to Section 8.3.5.4
Hepatic function will be closely 
monitored throughout the study.
Refer to Section 6.4.3,
Colitis
Refer to Section 8.3.5.1
Signs and symptom of colitis will be 
closely monitored,
Refer to Section 6.4.4.
Anaphylaxis
Refer to Section 8.3.5.2.
In case of Grade 3 or 4 allergic 
reaction, IP infusion will be stopped 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Histamine is a major mediator of 
anaphylactic/anaphylactoid 
responses in man, such as those 
induced by Cremophor EL, an 
excipient of AL101.
and infusion tubing from the subject 
will be disconnect. Refer to 
Section 6.4.1.
Glucocorticoids may be administered 
for treatment of infusion reaction and 
as premedication to prevent further 
infusion reaction. Refer to 
Section 6.6.1.
Keratoacanthoma
Refer to Section 8.3.5.3
Subjects will be closely monitored 
for skin changes throughout the 
study. Subjects will be counseled to 
avoid excessive sun and UV 
exposure during the study
Study Procedures
Infusion site reactions
Refer to Section 6.4.1.
Glucocorticoids may be administered 
for treatment of infusion reaction and 
as premedication to prevent further 
infusion reaction. Refer to 
Section 6.6.1.
2.3.2.
Benefit Assessment
Nonclinical and clinical data provide rationale for evaluating the potential clinical benefits of 
AL101 in subjects with TNBC for whom available standard of care is not providing durable 
response as defined by complete (CR) or partial response (PR). In a Phase 1 study (CA216003, 
NCT01653470), clinical activity of AL101 was shown in an unselected heavily treated patient 
population with solid tumors; confirmed objective responses were reported for 8 of the 22 
subjects (36.4%) with TNBC who were treated with AL101 in combination with various 
chemotherapy agents (1 subject with a CR and 7 subjects with PR). It is estimated that treatment 
with AL101 may have a positive impact in patients with Notch-activated recurrent or metastatic 
TNBC, who may thus derive benefit from this treatment.
2.3.3.
Overall Benefit Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this study, 
the potential risks identified in association with AL101 are justified as compared to the potential 
benefits that may be afforded to subjects with Notch-activated TNBC.
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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the efficacy of AL101 
monotherapy in subjects with 
Notch-activated recurrent or metastatic 
TNBC

Proportion of subjects who demonstrate an 
overall response rate (ORR), defined as PR 
+ CR as assessed by investigator based on 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1
Secondary

Efficacy - Secondary

Clinical benefit response rate (CBR) 
defined as CR +PR + stable disease (SD) 
by investigator review based on 
RECIST v1.1

Duration of response (DOR) by 
investigator review based on RECIST v1.1

Progression free survival (PFS)

Proportion of subjects who have PFS at 6 
months

Overall survival (OS)

Quality of life (QoL) as determined by 
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire 30 questions (EORTC 
QLQ-C30) and Breast Cancer 45 questions 
(EORTC QLQ-BR45)

To evaluate the safety and tolerability of 
AL101 monotherapy in subjects with 
recurrent or metastatic TNBC 

Frequency, duration and severity of 
treatment-emergent adverse events 
(TEAEs) and serious adverse events 
(SAEs)

Incidence of clinically significant 
abnormalities in laboratory parameters, 
electrocardiograms (ECGs), vital signs and 
physical examination
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Objectives
Endpoints
Exploratory

To characterize biomarkers as a measure 
of response to AL101 monotherapy, and 
overall prognosis

To establish correlation between positive 
Notch intracellular domain (NICD) 
immunohistochemistry (IHC) stain and 
Notch activating mutations

To establish the correlation between 
mutations in Notch and associated genes 
and response or resistance to 
investigational product

Change in quantity of circulating tumor 
cells (CTCs), and other biomarkers in 
CTCs

Predictive biomarkers of response or 
resistance to the investigational product 
will be explored:
-
IHC: Tumor specimens will be 
stained for NICD and other potential 
biomarkers.
-
NGS: Mutational analysis of tumor 
tissue samples, and potentially 
cfDNA and CTCs.
-
Gene expression analysis in tumor 
tissue samples.
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4.
OVERALL STUDY DESIGN
4.1.
Study Design
This is an open-label multicenter, Phase 2, Simon two-stage optimal design for targeted therapy 
study of single arm AL101 monotherapy in subjects with Notch-activated recurrent or metastatic 
TNBC whose disease has recurred or progressed after 3 or fewer lines of prior therapy.
The design will include a lead-in cohort with 6 subjects to ascertain safety of the investigational 
product (IP), AL101, 6 mg weekly (QW). The safety will be reviewed on a regular schedule 
(weekly calls with investigators, and quarterly reviews with the Data Monitoring Committee 
[DMC]). After the 6th subject is enrolled and completes 4 weeks of therapy (1 cycle), the results 
will be reviewed in aggregate and, if the safety is acceptable (as defined below), the study will 
continue at 6 mg administered QW. Note, if safety is not acceptable amongst the first 6 subjects 
dosed at 6 mg QW, the IP dose will be reduced to 4 mg QW. The decision on which dose to use 
for the remainder of the study will be determined after formal safety assessment with the 
investigators and the DMC.
Acceptable safety:
-
2 or fewer subjects experience Grade 3 or 4 diarrhea lasting more than 3 days
-
2 or fewer subjects experience another specific Grade 3 or 4 adverse event (AE) which is 
attributable to IP
After the lead-in phase with AL101 6 mg QW, the study will proceed to complete the described 
Simon two-stage design as shown in Figure 1 and described in Section 9.1.
Prior to entering the study, to determine eligibility, potential candidates who sign a separate 
pre-screening informed consent, will undergo pre-screening assessment for evaluation of Notch 
mutational status from a persistent locally advanced or metastatic lesion. If historical genotyping 
results from the last 2 years that identify a Notch-activated genetic alteration are available from a 
commercially available NGS assay or laboratory developed test (LDT), these results are 
acceptable to use for determining eligibility. In Europe any commercially available CE marked 
device can be used.
If acceptable genotyping results are not available, testing of a sample collected from a locally 
advanced or metastatic lesion must be conducted during pre-screening using a commercially 
available NGS assay, LDT or other validated investigational use only (IUO) clinical trial assay 
capable of detecting genetic alterations in the NOTCH 1/2/3/4 genes. For this purpose, tumor 
biopsy from within the last 2 years or fresh biopsy will be needed.
After signing an informed consent, all subjects will then undergo screening assessments to 
determine study eligibility over a 28-day Screening period. Eligibility criteria for study entry will 
be assessed locally by the investigator; radiographic scans at screening and from the prior 12 
months will be collected and held for possible future retrospective independent evaluation. 
Tumor tissue will need to be provided during the Screening period for confirmatory study-
specific testing.
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Starting on Cycle 1, Day 1, eligible subjects will be treated with IP intravenously (IV) QW, on 
Days 1, 8, 15 and 22 of each 28-day cycle. Treatment will continue until the occurrence of 
unequivocal radiographic disease progression per RECIST v1.1 as assessed by the investigator, 
or clear clinical progression as assessed by the investigator, or unacceptable toxicity, or other 
reasons for discontinuation.
All subjects will receive premedication with H1- and H2-blockers per institution guideline (refer 
to Section 6.6.1) and steroids as prophylaxis (refer to Section 6.6.2). Toxicity post-AL101 
administration will be managed as specified in Section 6.4.
During the Treatment period, subjects will undergo radiographic assessments every 8 weeks 
(±3 days) for review by the investigator. Radiographic scans will also be collected and held for 
possible future retrospective independent evaluation. Other assessments will be done as specified 
in the Schedule of Activities (Table 1). A repeat of tumor imaging will be required for the 
purposes of confirmation of response (i.e., partial response, and/or complete response). The 
confirmation scan should be no earlier than 4 weeks following the first indication of response.
Samples from tumor biopsies will be collected at screening from a locally advanced or metastatic 
lesion (fresh or archival within 2 years), and at Cycle 4 Day 1 ±28 days (provided that biopsy 
collection is medically safe and not contraindicated). If an archival tumor block or 25 unstained 
slides are not available, the subject will be required to have a fresh tumor sample obtained at 
screening. Biopsy samples will be evaluated by NGS for genomics, immunohistochemistry 
(IHC) for Notch intracellular domain (NICD) stain, and other biomarkers potentially related to 
sensitivity to AL101 or TNBC prognosis. Blood samples for pharmacokinetics (PK) and 
biomarker analysis will also be collected on the same day as the on-treatment biopsy.
All subjects will undergo end of study (EOS) visit 30 days post last treatment with IP and will be 
contacted by phone to determine survival status (refer to Section 4.4). In subjects who 
discontinued IP due to toxicity, radiographic imaging will be done every 3 months until disease 
progression or until the subject initiates another anti-cancer therapy.
4.2.
Scientific Rationale for Study Design
The study will utilize Simon two-stage optimal design for targeted therapy (Simon, 1989). This 
design allows determination of AL101 anti-tumor activity while minimizing the expected sample 
size. The study will also include a lead-in cohort to establish the safety of AL101 administered at 
6 mg QW with the described pre-medications as described in Section 6.6 and safety management 
as detailed in Section 6.4.
The primary endpoint, proportion of subjects with an ORR (CR+PR), was selected based on the 
FDA guidance from December 2018 on endpoints in oncology studies (FDA, 2018).
4.2.1.
Rationale for Study Population
The primary target population for this study is subjects with recurrent or metastatic TNBC. This 
population is selected based on the mechanism of action of AL101, nonclinical and preliminary 
clinical data with AL101, as well as the pathophysiology of TNBC. Based on preliminary 
nonclinical and clinical emerging data, Notch-activated TNBC patient populations are selected to 
receive AL101 as monotherapy.
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In TNBC patient-derived xenograft (PDX) tumor models, the presence of an activated Notch 
pathway signature and Notch mutations/fusions correlates with a significant response to AL101 
monotherapy (Broner, 2019). Therefore, the Sponsor will test the hypothesis that subjects 
diagnosed with TNBC bearing Notch-activated gene alterations responds to AL101 
monotherapy.
Importantly for the purposes of this study, the definition of TNBC has been evolving over the 
past few years. According to the 2010 guidelines by the American Society of Clinical Oncology 
(ASCO) and the College of American Pathologists (CAP), to qualify for TNBC, estrogen 
receptor (ER)/progesterone receptor positivity was defined as ≤1% positively stained cells by 
IHC (Hammond, 2010). However, several studies show that tumors with 1% < ER < 10% behave 
similarly to those with ER ≤ 1% (Deyarmin, 2013; Prabhu, 2014; Yi, 2014). Therefore, Fujii et 
al. recommends to define TNBC as human epidermal growth factor receptor 2 (HER2) negative 
BC with ER and/or progesterone receptor less than 10% (Fujii, 2016). Thus, subjects with less 
than 10% IHC staining of ER/progesterone receptor will be eligible to participate.
4.3.
Justification for Dose
The dose selected for this study (6 mg QW) is based on nonclinical studies, prior clinical studies 
conducted by BMS (the previous developer) (CA216001, CA216002 and CA216003) and 
preliminary outcome from the ongoing ACCURACY study conducted by Ayala 
(NCT03691207). Please also refer to the Investigator’s Brochure for further information.
Study CA216001 was a first in human dose escalation study which evaluated doses ranging from 
0.4 mg QW to 8.4 mg QW. In the initial dose-escalation, there were no dose limiting toxicities 
(DLTs) noted in 4 subjects at 6 mg QW. Dose escalation was continued to 8.4 mg QW and 
DLTs, including a Grade 5 liver failure in one subject, were noted. The case of liver failure was 
complicated by pre-existing liver injury and possible contribution of an investigational 
nucleoside analogue, the subject had previously received, known to cause delayed liver toxicity. 
Consequently, an additional 10 subjects were enrolled at the 6 mg QW dose. There were 4 DLTs 
observed amongst 4 of these additional subjects including 2 subjects with Grade 3 diarrhea, 1 
subject with Grade 3 vomiting/Grade 3 lipase elevation, and 1 subject with Grade 3 large 
intestinal ulcer with a non-treatment related Grade 3 infectious colitis. Based on this data, the 
previous sponsor assessed the RP2D as 4 mg QW.
However, upon careful review of these data, Ayala concluded that, with proper control of 
diarrhea, 2 of the DLTs which were noted at 6 mg QW could probably have been controlled so 
that they were potentially not DLTs. Importantly this is further substantiated by the observation 
in the ongoing ACCURACY study that (AL-ACC-01), with proactive control of diarrhea, there 
was only a 3% (2/34) incidence of Grade 3 diarrhea as opposed to the 19% (8/43) incidence 
noted in CA216001. The proactive control of diarrhea is delineated below and includes frequent 
and early use of loperamide followed by a low threshold to use steroids.
Furthermore, study CA216002 evaluated subjects with T-ALL/T-LL at the 6 mg QW dose. The 
subjects in this study tolerated the 6 mg QW dose well with no reported DLTs.
From a mechanistic perspective interest in using the higher dose of AL101 is driven by PK and 
pharmacodynamic (PD) results from the Phase 1 Study CA216001 indicate that AL101 exposure 
(Cmax and area under the curve [AUC]) increases with approximately linear kinetics for QW 
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dosing across all doses tested. Furthermore, PD results (Hes1 expression in peripheral whole 
blood) from Study CA216001 indicate greater maximum effect and duration of target inhibition 
when increasing the QW dose from 2.4 mg to 4 mg to 6 mg and appears to reach a plateau at 8.4 
mg QW. Most notably, the 6 mg dose achieved a considerably larger reduction in Hes1 and Hes4 
than the 4 mg dose. This observation further supports using the 6mg QW dose.
Hence, the data from the 3 studies mentioned above (CA216001, CA216002 and ACCURACY) 
indicate that the 6 mg QW dose appears to be tolerated, especially if one implements proactive 
steps to manage the diarrhea. In addition, the PD data strongly suggests that the PD markers, Hes1 
and Hes4, will be decreased to a much larger extent at 6 mg than at 4 mg, indicating better 
inhibition of Notch. In this new trial, safety will be closely monitored with specific instructions on 
how to control diarrhea, dose modification guidelines, and close monitoring of the subjects.
In the Phase 2 ACCURACY study, preliminary results have been reported. As of October 11, 
2019, the safety analysis set included 29 subjects with adenoid cystic carcinoma. The most 
frequently reported AEs (>30% of all treated subjects), regardless of causality, were nausea, 
fatigue, diarrhea and vomiting. SAEs were reported for 14 subjects (48.3%) with pneumonia 
reported by 3 subjects (10.3%), all other events were single incidences. Treatment-related SAEs 
included infusion site reactions (2 reactions in one subject) and keratoacanthoma (each, 1 
subject, 3.4%). The ACCURACY study is ongoing and expanded to include AL101 6 mg QW 
dosing schedule.
The observed safety profile of AL101 in the ACCURACY study to date suggests a lower rate of 
TEAEs of Grade 3 and above than previously reported for AL101 Phase 1 studies conducted by 
the previous developer. Notably, using the toxicity management guidelines for gastrointestinal 
(GI) adverse events in this protocol (outline in Section 6.4), the rate of Grade 3 diarrhea was 
reduced to 3.4% vs. 19.1% in the ongoing ACCURACY study vs. study CA216001, 
respectively. This suggests that with a rigorous control of GI toxicity, a dose of 6 mg is safe to 
administer to subjects with advanced cancer.
4.4.
Study Duration
For each subject, the study is expected to last as follows:
Screening period: 
Up to 28 days 
Treatment period: 
Until disease progression, unacceptable toxicity, or consent withdrawal
EOS: 
30 days after the last administration of IP
Long term follow-up: 
Every 3 months for the first year after EOS, then every 6 months for 
the next 2 years and then annually
4.5.
End of Study Definition
A subject is considered to have completed the study if he/she has completed EOS visit.
The end of the study is defined as the date of the last visit of the last subject in the study.
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5.
ELIGIBILITY CRITERIA
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
To be eligible for participation in this study, subjects must meet all the following criteria:
Age
1. At least 18 years of age (inclusive) at the time of signing the Informed Consent Form 
(ICF).
Type of Subject and Disease Characteristics
2. Have at least one measurable lesion per RECIST v1.1.
3. Have formalin-fixed paraffin-embedded (FFPE) tissue available from a metastatic lesion; 
a tumor block or 25 unstained slides from an archived (within 2 years) or fresh tumor 
samples (core or punch needle biopsy) are acceptable.
4. Documented tumor progression following no more than 3 lines of systemic 
chemotherapy, PARP inhibitor therapy or immunotherapy for metastatic disease, as 
appropriate. Of note, neoadjuvant and adjuvant therapy will not count as prior lines of 
therapy.
5. Histologically confirmed diagnosis of inoperable locally advanced or metastatic TNBC 
defined as ER and progesterone receptor staining <10%, and HER2-negative defined as 
IHC 0 to 1+
Note, if IHC is equivocal then do  fluorescence in situ hybridization (FISH) or in situ 
hybridization (ISH); negative will be acceptable. 
Note: if FISH or ISH is equivocal then further assessment is allowed with Sponsor 
written approval.
6. Documented Notch activation from tumor biopsy results from within the last 2 years 
from a commercially available NGS assay, LDT or other validated IUO clinical trial 
assay.
Gender and Reproductive Considerations
7. Female or Male subjects.
8. Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to the start of IP and must agree to have a pregnancy test at least every cycle 
(4 weeks). An extension up to 72 hours is permissible in situations where results cannot 
be obtained within the standard 24-hour window.
Contraception use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
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9. WOCBP must agree to use a highly effective birth control during the study (prior to the 
first dose with AL101 and for 120 days after the last dose), if conception is possible 
during this interval. Female subjects are considered to not be of childbearing potential if 
they have a history of hysterectomy or are post-menopausal defined as no menses for 
12 months without an alternative medical cause.
10. Male subjects with partners who are WOCBP should use a combination of the methods 
specified in Section 10.4 for the women along with a male condom during the study and 
for 120 days after the last dose of IP, unless permanently sterile by bilateral 
orchidectomy.
Informed Consent
11. Capable of giving signed informed consent form (ICF) which includes compliance with 
the requirements and restrictions listed in the ICF and in this protocol.
5.2.
Exclusion Criteria
The subjects must be excluded from participating in the study if they meet any of the following 
criteria:
Medical Conditions
1. A known additional malignancy that is progressing or requires active treatment that is 
considered medically active and may interfere in the ability to detect responses in this 
subject. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin that have undergone potentially curative therapy or in situ cervical cancer. Any 
exceptions should be discussed with the Sponsor’s Medical Monitor.
2. BC that, in the opinion of the investigator, is considered amenable to potentially curative 
treatment.
3. Symptomatic central nervous system (CNS) metastases. Subjects with asymptomatic 
CNS metastases as well as those with previously treated CNS metastases are eligible for 
enrollment in the study if at least 28 days has elapsed since definitive treatment (either 
surgery, whole brain radiotherapy,  stereotactic radiation), steroid therapy is either not 
required or dose has been weaned off over last 14 days, and the subject is deemed 
clinically stable by the investigator.
4. Current or recent (within 2 months of IP administration) gastrointestinal (GI) disease or 
disorders that increase the risk of diarrhea, such as inflammatory bowel disease and 
Crohn’s disease. Non-chronic conditions (e.g., infectious diarrhea) that are completely 
resolved for at least 2 weeks prior to starting IP are not exclusionary.
5. Developed immune-mediated colitis with immunotherapy unless resolved to G1 or lower 
and without requirement of steroid treatment for at least 14 days prior to first dose of IP.
6. Peripheral neuropathy  Grade 2 for at least 14 days prior to first dose of IP.
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7. Evidence of uncontrolled, active infection, requiring systemic anti-bacterial, anti-viral or 
anti-fungal therapy ≤7 days prior to administration of IP such as known active infection 
with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
8. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac or pulmonary 
function or uncontrolled diabetes) or any important medical illness or abnormal 
laboratory finding that would, in the investigator’s judgment, increase the risk to the 
subject associated with his or her participation in the study.
9. Pregnant or breastfeeding or expecting to conceive children within the projected duration 
of the study.
Diagnostic Assessments
10. Eastern Cooperative Oncology Group (ECOG) performance status ≥2.
11. Abnormal organ and marrow function defined as:
a.
neutrophils <1000/mm3,
b. platelet count <75,000/mm3,
c.
hemoglobin <8 g/dL,
d. total bilirubin >1.5upper limit of normal (ULN) (except known Gilbert’s syndrome 
whereby the total bilirubin must be < 5 mg/dL),
e.
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >2.5ULN 
OR >5ULN for subjects with liver metastases,
f.
serum creatinine > ULN and creatinine clearance (CrCl) <50 mL/min (calculation of 
CrCl will be based on acceptable institution standard),
g. uncontrolled triglyceride ≥Grade 2 elevations per CTCAE v5.0 (>300 mg/dL or 
>3.42 mmol/L).
12. Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia 
or active conduction system abnormalities.
13. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥480 msec.
Prior/Concurrent Therapy
14. Completed palliative radiation therapy < 7 days prior to initiating IP.
15. Prior treatment with gamma secretase inhibitors. Prior treatment with anti-Notch 
antibodies may be allowed upon discussion with the Sponsor’s medical monitor.
16. Last chemotherapy, biologic, or investigational therapy agent at least 4 weeks or 5 half-
lives (whichever is shorter) prior to initiating IP; at least 6 weeks if the last regimen 
included BCNU or mitomycin C. Prior treatment with investigational monoclonal 
antibody will be reviewed case-by-case by the Sponsor.
17. Receiving chronic systemic steroid therapy (in dosing exceeding 10 mg/day of 
prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days 
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prior to the first dose of IP. The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor.
18. Use of strong inhibitors of CYP3A4 within 1 week or 5 half-lives (whichever is longer) 
or strong inducers of CYP3A4 within 2 weeks or 5 half-lives (whichever is longer). Refer 
to Section 10.5.
Other Exclusions
19. Concurrent enrolment in another clinical study, unless it is an observational (non-
interventional) clinical study or during the follow-up period of an interventional study.
20. Life expectancy of less than 3 months.
21. Hypersensitivity to AL101 and any of its excipients.
5.3.
Lifestyle Consideration
5.3.1.
Dietary and Other Restrictions

Grapefruit and Seville oranges and their juices can inhibit CYP3A4 and should not be 
consumed excessively while on study.

Subjects should be cautioned to avoid sun exposure and take appropriate protective 
precautions.

Because of the potential for reproductive adverse effects, options for sperm and egg banking 
should be discussed with the subject, if appropriate.

Subjects should be provided loperamide at the first dosing visit, instructed on its use and 
counseled to contact their clinician at the first occurrence of diarrhea or loose stools.

Because of the potential for Notch-related effects on gastrointestinal mucosa, gastric ulcer 
prophylaxis (e.g. with a proton pump inhibitor) should be considered for all subjects.
Refer to the AL101 IB for further information.
5.4.
Subject Identification
Each subject who signs informed consent will be assigned a subject number via the Interactive 
Web/Voice Response System (IXRS). This number will be used as the primary identification for 
the complete duration of the study. After the subject signed the informed consent form (ICF), the 
investigator will enter the subject into the Screening section of the electronic case report form 
(eCRF).
5.5.
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
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authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE.
Re-screening/re-assessment outside the Screening period will be possible on a case-by-case basis 
following Sponsor approval. Subjects allowed to be re-screened will be assigned a new screening 
number (with referral in eCRF to the previous screening number); such subjects will be 
determined a screen failure after the second screening confirmed the subject is ineligible.
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6.
INVESTIGATIONAL PRODUCT AND CONCOMITANT 
THERAPY
Investigational product is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study subject according to the 
study protocol.
6.1.
Investigational Product Administered
AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling.
Table 2
Investigational product
Intervention Name
AL101 
Type 
Small Molecule
Dose Formulation
Solution for infusion
Unit Dose 
Strength(s)
1.2 mg/mL
Dosage Level(s)
4 or 6 mg (1.2 mg/mL x 5mL) (refer to Figure 1 and Section 4.1 for dose 
determination)
Frequency: Weekly (QW) on Days 1, 8, 15 and 22 of each 28-day cycle
Route of 
Administration
AL101 will be administered using an IV infusion pump over 60 minutes; time 
windows of -5 minutes to +15 minutes are permitted. The connection between 
the tubing from the infusion pump to the subject should be close to the 
insertion of the intravenous catheter.
The exact duration of infusion should be recorded in both source documents 
and eCRFs. The start time of dose administration will be called “0” hour. If an 
infusion is extended, interrupted or discontinued prior to completion, the 
duration and the reason for any dose extension, interruption or discontinuation 
will be recorded in the eCRF.
Preparation
Prior to IV administration, the AL101 6 mg (1.2 mg/mL x 5mL) is diluted in a 
250 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline) 
or 5% Dextrose Injection, USP (D5W).
Only diethylhexyl phthalate-free bags and infusion sets can be used to 
administer solutions. Aseptic practices should be followed when handling, 
preparing, and administering the infusion solutions because the drug vial does 
not contain antibacterial preservatives or bacteriostatic agents. A sufficient 
excess of drug product is included in each vial to account for withdrawal 
losses.
Refer to Study Pharmacy Manual for more details.
IMP definition
A new drug that is used in a clinical investigation (FDA)
Sourcing
AL101 is manufactured by Bristol-Myers Squibb.
Investigational product will be provided to the site centrally by the Sponsor or 
designated representative (Fisher Clinical Services, USA).
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Intervention Name
AL101 
Packaging and 
Labeling
AL101 is supplied as a single-use sterile solution 5 mL per vial (1.2 mg/mL; 
equivalent of 6 mg per vial) for IV administration; The secondary packaging 
and labeling of IP will be performed by Fisher Clinical Services.
All packaging and labeling operations for IP will be performed according to 
Good Manufacturing Practices for Medicinal Products and the relevant 
regulatory requirements. Label text for the AL101 vial will at a minimum 
include the protocol number, the contents of the vial, batch number, storage 
conditions, and Sponsor name and address.
Former Name(s) 
or Alias(es)]
BMS-906024
6.2.
Handling, Storage and Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for IP received and any discrepancies are reported and resolved 
before use of IP.
2. Only subjects enrolled in the study may receive IP and only authorized site staff may 
supply or administer IP. All IP must be stored in a secure, environmentally controlled, 
and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
4. At the end of the study, the monitor will conduct a final drug reconciliation for all 
subjects and the study site overall. All records of IP administration, accountability 
records and IP disposition records will be examined and reconciled by the study monitor. 
Further details will be provided in the Study Pharmacy Manual.
Further guidance and information for the final disposition of unused IP are provided in the 
Pharmacy Manual.
6.3.
Compliance of Investigational Product
When subjects are dosed at the site, they will receive IP directly from the investigator or 
designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and recorded in the eCRF. The dose of IP and study 
subject identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the IP.
6.4.
AL101 Dose Modification and Toxicity Management Guidelines
Dose modification associated with AL101 is described below in Table 3.
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The causality assessment (related/not related) as defined in Section 10.3.4 will be used by the 
investigator for assessing drug-related non-hematological Grade 3 (except isolated Grade 3 
electrolyte abnormality that are not associated with clinical signs or symptoms and are reversed 
with appropriate medical intervention within 48 hours) and hematological Grade 4 toxicities. If 
there is a relationship to the drug, this will lead to a 1 dose level reduction for AL101. For easily 
manageable Grade 1 or 2 toxicity, no dose reductions are required, but careful observation and 
treatment is required. Dose modification of intolerable Grade 2 toxicity will be evaluated on a 
case-by-case basis with the Sponsor. Re-escalation of the dose following a dose reduction is not 
allowed, however, subject can be re-treated at the lower dose. The subject can resume treatment 
with AL101 after resolution of signs and symptoms to Grade 1 or a baseline level (whichever is 
greater) at the discretion of the investigator. Maximum AL101 treatment interruption allowed is 
28 days; treatment interruption longer than 28 days will result in discontinuation of subject from 
the study. Additional treatment guidelines may be implemented by the investigators, with 
agreement of the Sponsor/Medical Monitor, as needed to ensure subject safety.
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Table 3
Dose Modification Criteria for AL101
AL101 modification at next dose
Dose Modification Criteria for 
AL101 -Related Adverse Events
Dose 6 mg QW
Dose 4 mg QW
Grade 4 neutropenia lasting ≥ 7 
days 
Decrease AL101 dose to 4 mg QW for first episode 
and to 2.4 mg QW for second episode.
Decrease AL101 dose to 2.4 mg QW
Grade 3 or 4 febrile neutropenia 
Decrease AL101 dose to 4 mg QW for first episode 
and to 2.4 mg QW for second episode.
Decrease AL101 dose to 2.4 mg QW
Grade 4 thrombocytopenia or ≥
Grade 3 thrombocytopenia with 
significant bleeding 
Decrease AL101 dose to 4 mg for first episode and 
to 2.4 mg QW for second episode
Decrease AL101 dose to 2.4 mg QW
Grade 1 diarrhea 
No change in AL101 dose.
Guidelines for the management of diarrhea:

Loperamide 4 mg at the first onset of 
diarrhea, then 2 mg every 2 hours around-
the-clock until diarrhea free for at least 12 
hours. Subjects may take loperamide 4 mg 
every 4 hours during the night. These doses 
should not be used for more than 48 hours 
due to the risk of paralytic ileus.

For subjects that cannot tolerate loperamide 
or do not get adequate relief with maximum 
doses, standard doses of LOMOTIL® 
(diphenoxylate/atropine) may be added or 
used instead of loperamide.

Additional antidiarrheal measures, such as 
octreotide, may be used at the discretion of 
the investigator or treating physician.
No change in AL101 dose.
Guidelines for the management of diarrhea:

Loperamide 4 mg at the first onset of 
diarrhea, then 2 mg every 2 hours around-
the-clock until diarrhea free for at least 12 
hours. Subjects may take loperamide 4 mg 
every 4 hours during the night. These doses 
should not be used for more than 48 hours 
due to the risk of paralytic ileus.

For subjects that cannot tolerate loperamide 
or do not get adequate relief with maximum 
doses, standard doses of LOMOTIL® 
(diphenoxylate/atropine) may be added or 
used instead of loperamide.

Additional antidiarrheal measures, such as 
octreotide, may be used at the discretion of 
the investigator or treating physician.
Grade 2 diarrhea 
Guidelines for the management of diarrhea:
Guidelines for the management of diarrhea:
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AL101 modification at next dose
Dose Modification Criteria for 
AL101 -Related Adverse Events
Dose 6 mg QW
Dose 4 mg QW

Evaluate subject carefully including 
laboratory assessments (chemistry, liver 
function tests and lipase) 

Loperamide 4 mg at the first onset of 
diarrhea, then 2 mg every 2 hours around-
the-clock until diarrhea free for at least 12 
hours. Subjects may take loperamide 4 mg 
every 4 hours during the night. These doses 
should not be used for more than 48 hours 
due to the risk of paralytic ileus.

For subjects that cannot tolerate loperamide 
or do not get adequate relief with maximum 
doses, standard doses of LOMOTIL®
(diphenoxylate/atropine) may be added or 
used instead of loperamide. 

Additional antidiarrheal measures, such as 
octreotide, may be used at the discretion of 
the investigator or treating physician 
If the above measures have not worked, or subject 
has progressed to Grade 2, or after Grade 1 with no 
improvement within 3 days with maximum doses of 
loperamide:

Subject may be treated with dexamethasone 
at a dose of 8 mg every 8 hours (Q8h) for 
up to 5 days.  If still no improvement in 
symptoms, the subject may continue with 
the dexamethasone or consider switching to 
budesonide 9 mg once daily (QD). Refer to 
Section 6.6.2 for additional instructions on 
premedication with steroids.

Evaluate subject carefully including 
laboratory assessments (chemistry, liver 
function tests and lipase)

Loperamide 4 mg at the first onset of 
diarrhea, then 2 mg every 2 hours around-
the-clock until diarrhea free for at least 12 
hours. Subjects may take loperamide 4 mg 
every 4 hours during the night. These doses 
should not be used for more than 48 hours 
due to the risk of paralytic ileus.

For subjects that cannot tolerate loperamide 
or do not get adequate relief with maximum 
doses, standard doses of LOMOTIL®
(diphenoxylate/atropine) may be added or 
used instead of loperamide. 

Additional antidiarrheal measures, such as 
octreotide, may be used at the discretion of 
the investigator or treating physician 
If the above measures have not worked, or subject 
has progressed to Grade 2, or after Grade 1 with no 
improvement within 3 days with maximum doses of 
loperamide:

Subject may be treated with dexamethasone 
at a dose of 8 mg Q8h for up to 5 days.  If 
still no improvement in symptoms, the 
subject may continue with the 
dexamethasone or consider switching to 
budesonide 9 mg QD. Refer to Section 6.6.2
for additional instructions on premedication 
with steroids.
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AL101 modification at next dose
Dose Modification Criteria for 
AL101 -Related Adverse Events
Dose 6 mg QW
Dose 4 mg QW
Dose modifications for AL01:
Interrupt AL101 until resolution to ≤ Grade 1 (refer 
to Section 6.4.2 and above for management 
guidelines for diarrhea).
Change dose regimen to 6 mg 2 weeks on / 1 week 
off for first episode
Decrease AL101 dose to 4 mg QW for second 
episode and to 2.4 mg QW for third episode.
If the diarrhea does not resolve to Grade 1 by 14 
days, the subject will be discontinued from IP (refer 
to Section 7.2 for handing IP discontinuation).
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation).
Dose modifications for AL01:
Interrupt AL101 until resolution to ≤ Grade 1 (refer 
to Section 6.4.2 and above for management 
guidelines for diarrhea).
Decrease AL101 dose to 2.4 mg QW.
If the diarrhea does not resolve to Grade 1 by 14 
days, the subject will be discontinued from IP (refer 
to Section 7.2 for handing IP discontinuation).
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation).
Grade 3 diarrhea
Guidelines for the management of diarrhea:

Evaluate subject carefully including 
laboratory assessments (chemistry, liver 
function tests and lipase)

Loperamide 4 mg at the first onset of 
diarrhea, then 2 mg every 2 hours around-
the-clock until diarrhea free for at least 12 
hours. Subjects may take loperamide 4 mg 
every 4 hours during the night. These doses 
should not be used for more than 48 hours 
due to the risk of paralytic ileus.

For subjects that cannot tolerate loperamide 
or do not get adequate relief with maximum 
doses, standard doses of LOMOTIL®
Guidelines for the management of diarrhea:

Evaluate subject carefully including 
laboratory assessments (chemistry, liver 
function tests and lipase) 

Loperamide 4 mg at the first onset of 
diarrhea, then 2 mg every 2 hours around-
the-clock until diarrhea free for at least 12 
hours. Subjects may take loperamide 4 mg 
every 4 hours during the night. These doses 
should not be used for more than 48 hours 
due to the risk of paralytic ileus.

For subjects that cannot tolerate loperamide 
or do not get adequate relief with maximum 
doses, standard doses of LOMOTIL®
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AL101 modification at next dose
Dose Modification Criteria for 
AL101 -Related Adverse Events
Dose 6 mg QW
Dose 4 mg QW
(diphenoxylate/atropine) may be added or 
used instead of loperamide. 

Additional antidiarrheal measures, such as 
octreotide, may be used at the discretion of 
the investigator or treating physician 
If the above measures have not worked, or subject 
has progressed to Grade 3:

Treat with dexamethasone at a dose of 8 
mg Q8h for up to 5 days.  If still no 
improvement in symptoms, the subject may 
continue with the dexamethasone or 
consider switching to budesonide 9 mg QD. 
Refer to Section 6.6.2 for additional 
instructions on premedication with steroids.
Dose modifications for AL01:
Interrupt AL101 until resolution to ≤ Grade 1 (refer 
to Section 6.4.2 and above for management 
guidelines for diarrhea).
Change dose regimen to 6 mg 2 weeks on / 1 week 
off for the first episode.
Decrease AL101 dose to 4 mg QW for second 
episode and to 2.4 QW mg for third episode.
If the diarrhea does not resolve to Grade 1 by 14 
days, the subject will be discontinued from IP (refer 
to Section 7.2 for handing IP discontinuation).
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation).
(diphenoxylate/atropine) may be added or 
used instead of loperamide. 

Additional antidiarrheal measures, such as 
octreotide, may be used at the discretion of 
the investigator or treating physician 
If the above measures have not worked, or subject 
has progressed to Grade 3:

Treat with dexamethasone at a dose of 8 
mg Q8h for up to 5 days.  If still no 
improvement in symptoms, the subject may 
continue with the dexamethasone or 
consider switching to budesonide 9 mg QD. 
Refer to Section 6.6.2 for additional 
instructions on premedication with steroids.
Dose modifications for AL01:
Interrupt AL101 until resolution to ≤ Grade 1 (refer 
to Section 6.4.2 and above for management 
guidelines for diarrhea).
Decrease AL101 dose to 2.4 mg QW.
If the diarrhea does not resolve to Grade 1 by 14 
days, the subject will be discontinued from IP (refer 
to Section 7.2 for handing IP discontinuation).
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation).
Grade 4 diarrhea
Guidelines for the management of diarrhea:
Guidelines for the management of diarrhea:
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AL101 modification at next dose
Dose Modification Criteria for 
AL101 -Related Adverse Events
Dose 6 mg QW
Dose 4 mg QW

Evaluate subject carefully including 
laboratory assessments (chemistry, liver 
function tests and lipase) 

Loperamide 4 mg at the first onset of 
diarrhea, then 2 mg every 2 hours around-
the-clock until diarrhea free for at least 12 
hours. Subjects may take loperamide 4 mg 
every 4 hours during the night. These doses 
should not be used for more than 48 hours 
due to the risk of paralytic ileus.

For subjects that cannot tolerate loperamide 
or do not get adequate relief with maximum 
doses, standard doses of LOMOTIL®
(diphenoxylate/atropine) may be added or 
used instead of loperamide. 

Additional antidiarrheal measures, such as 
octreotide, may be used at the discretion of 
the investigator or treating physician

Treat with dexamethasone at a dose of 
8 mg every Q8h for up to 5 days.  If still no 
improvement in symptoms, the subject may 
continue with the dexamethasone or 
consider switching to budesonide 9 mg QD. 
Refer to Section 6.6.2 for additional 
instructions on premedication with steroids. 
If the above measures have not worked, or subject 
has progressed to Grade 4, consult GI as necessary 
to evaluate for colitis.
Dose modifications for AL01:

Evaluate subject carefully including 
laboratory assessments (chemistry, liver 
function tests and lipase) 

Loperamide 4 mg at the first onset of 
diarrhea, then 2 mg every 2 hours around-
the-clock until diarrhea free for at least 12 
hours. Subjects may take loperamide 4 mg 
every 4 hours during the night. These doses 
should not be used for more than 48 hours 
due to the risk of paralytic ileus.

For subjects that cannot tolerate loperamide 
or do not get adequate relief with maximum 
doses, standard doses of LOMOTIL®
(diphenoxylate/atropine) may be added or 
used instead of loperamide. 

Additional antidiarrheal measures, such as 
octreotide, may be used at the discretion of 
the investigator or treating physician 

Treat with dexamethasone at a dose of 8 
mg Q8h for up to 5 days.  If still no 
improvement in symptoms, the subject may 
continue with the dexamethasone or 
consider switching to budesonide 9 mg QD. 
Refer to Section 6.6.2 for additional 
instructions on premedication with steroids.
If the above measures have not worked, or subject 
has progressed to Grade 4, consult GI as necessary 
to evaluate for colitis.
Dose modifications for AL01:
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AL101 modification at next dose
Dose Modification Criteria for 
AL101 -Related Adverse Events
Dose 6 mg QW
Dose 4 mg QW
Permanently discontinue IP (refer to Section 7.2 for 
handing IP discontinuation)
Permanently discontinue IP (refer to Section 7.2 for 
handing IP discontinuation)
Grade 2 Diagnosed or suspected 
clinically significant GI bleeding 
or unexplained drop in 
hemoglobin
Interrupt AL101, perform appropriate diagnosis and 
treatment.
If GI bleeding is considered related to AL101, 
decrease AL101 to 4 mg QW for first episode and 
to 2.4 mg QW for second episode.
If colitis is suspected, please refer to 
Section 6.4.3.1, Table 4 for management guidelines 
for colitis).
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation)..
Interrupt AL101, perform appropriate diagnosis and 
treatment.
If GI bleeding is considered related to AL101, 
decrease AL101 to 2.4 mg QW.
If colitis is suspected, please refer to 
Section 6.4.3.1, Table 4 for management guidelines 
for colitis).
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation)..
Grade 3 or 4 gastric hemorrhage 
Permanently discontinue AL101 (refer to 
Section 7.2 for handing IP discontinuation)
Permanently discontinue AL101 (refer to 
Section 7.2 for handing IP discontinuation)
QTcF > 500 msec confirmed by at 
least one repeat ECG and at least 
50 msec above baseline 
Interrupt AL101 if needed to optimize electrolyte 
management. 
If persists after electrolyte optimization (including 
dose modification of AL101 if necessary), 
discontinue IP (refer to Section 7.2 for handing IP 
discontinuation).
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation)..
Interrupt AL101 if needed to optimize electrolyte 
management. 
If persists after electrolyte optimization (including 
dose modification of AL101 if necessary), 
discontinue IP (refer to Section 7.2 for handing IP 
discontinuation).
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation).
AST or ALT > 5 times the 
institutional ULN 
Interrupt AL101 until resolution to ≤ Grade 1 and 
then decrease dose to 4 mg QW for first episode 
and to 2.4 mg QW for second episode.
Interrupt AL101 until resolution to ≤ Grade 1 and 
then decrease dose to 2.4 mg QW.
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AL101 modification at next dose
Dose Modification Criteria for 
AL101 -Related Adverse Events
Dose 6 mg QW
Dose 4 mg QW
Refer to Section 6.4.3 for hepatic function 
abnormalities and Figure 2 for drug-induced liver 
toxicity management.
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation)..
Refer to Section 6.4.3 for hepatic function 
abnormalities and Figure 2 for drug-induced liver 
toxicity management.
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation)..
Hy’s law cases (e.g. drug induced 
liver injury; DILI) as defined in 
Section 6.4.3.1 and assessed by the 
investigator and Sponsor
Immediately discontinue IP (refer to Section 7.2 for 
handing IP discontinuation)
Immediately discontinue IP (refer to Section 7.2 for 
handing IP discontinuation)
Triglyceride Grade 3 elevations 
that persist after 4 weeks of 
medical management
Interrupt AL101 until resolution to ≤ Grade 1 and 
then decrease dose to 4 mg QW for first episode 
and to 2.4 mg QW for second episode.
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation)..
Interrupt AL101 until resolution to ≤ Grade 1 and 
then decrease dose to 2.4 mg QW.
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation).
Infusion-related reaction 
For dose modification and management of infusion-
related reactions, refer to Section 6.4.1.
For dose modification and management of infusion-
related reactions, refer to Section 6.4.1.
Any other AL101-related  Grade 
3 nonhematologic adverse event 
except electrolyte abnormalities 
that may be managed with 
supplements
Interrupt AL101 until resolution to ≤ Grade 1 and 
then change dose regimen to 6 mg 2 weeks on / 1 
week off for the first episode.
Decrease AL101 dose to 4 mg QW for second 
episode and to 2.4 mg QW for third episode.
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation)..
Interrupt AL101 until resolution to ≤ Grade 1 and 
then decrease dose to 2.4 mg QW.
If treatment interruption is longer than 28 days, the 
subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation).
Grade 4 non-hematologic AEs 
including Grade 4 non-
Permanently discontinue from IP (refer to 
Section 7.2 for handing IP discontinuation).
Permanently discontinue from IP (refer to 
Section 7.2 for handing IP discontinuation).
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AL101 modification at next dose
Dose Modification Criteria for 
AL101 -Related Adverse Events
Dose 6 mg QW
Dose 4 mg QW
hematologic lab abnormalities 
lasting > 72 hours
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6.4.1.
Treatment of Infusion Reactions
In case of hypersensitivity reactions, the investigator should institute treatment measures deemed 
medically appropriate in accordance with current medical practice and treatment guidelines. The 
following treatment recommendations are based on prior experience with Taxol® (containing 
Cremophor® EL)1; these and/or other measures deemed medically necessary should be 
implemented based on the judgment of the investigator. To reduce the risk of infusion reactions 
caused by Cremophor EL, refer to refer to Section 6.6.1.
Note that the “Grades” listed below do not correspond to NCI CTCAE v5.0 criteria (which are 
based on response to intervention, and thus are not used here to recommend specific 
interventions). For the purpose of AE reporting and for determining the need for dose 
modifications, NCI CTCAE v5.0 grading for allergic reaction should be used.

Grade 1 allergic reaction/hypersensitivity (e.g., transient flushing, rash, drug fever 
< 38°C):

Supervise at the bedside.

Report to Sponsor as an adverse event of special interest (AESI)

Grade 2 allergic reaction/hypersensitivity (e.g., urticaria, drug fever  38°C, rash, 
flushing, dyspnea):

Interrupt the infusion and disconnect infusion tubing from subject,

Administer IV antihistamines (diphenhydramine 25 to 50 mg and famotidine 20 
to 40 mg or class equivalents),

After recovery from symptoms, resume the infusion at a half of the infusion rate 
and if no further symptoms appear, complete the administration of the dose. A 
target infusion time of up to 3 hours may be appropriate in some cases.

Report to Sponsor as an AESI

Grade 3 or 4 allergic reaction/hypersensitivity (e.g., symptomatic bronchospasm 
requiring parenteral medication(s) with or without urticaria; allergy-related 
edema/angioedema; anaphylaxis; hypotension):

Stop the infusion with AL101 and disconnect infusion tubing from subject,

Administer epinephrine, antihistamines, and nebulized bronchodilators as 
medically indicated,

Consider IV steroids which may prevent recurrent or ongoing reactions,

Report to Sponsor as a serious adverse event (Section 8.3.4),
1 Taxol (paclitaxel) label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf
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
Report to Sponsor as an AESI

Discontinue the subject from IP for a Grade 4 or for a second episode of a Grade 
3 reaction.
Other symptoms associated with hypersensitivity reactions include facial flushing, chest pain and 
tightness, back pain and GI symptoms, leg pain and cough.
Retreatment after a Grade 3 or greater hypersensitivity reaction despite premedication should be 
discussed between the Sponsor’s Medical Monitor and investigator prior to retreatment. If 
treatment interruption is longer than 28 days, the subject will be discontinued from IP.
6.4.2.
Guidelines for Management of Diarrhea
The guidelines for the management of diarrhea are included in Table 3 and are not meant to 
replace the clinical judgment of the investigator / treating physician(s) or an institutional diarrhea 
management protocol which adheres to most current medical standards.
1. Treat with loperamide
Loperamide should be started at the earliest sign of (1) a poorly formed or loose stool, (2) the 
occurrence of 1 to 2 more bowel movements than usual in 1 day, or (3) an increase in stool 
volume or liquidity. Loperamide may be taken in the following manners: 4 mg at the first onset 
of diarrhea, then 2 mg every 2 hours around-the-clock until diarrhea free for at least 12 hours. 
Subjects may take loperamide 4 mg every 4 hours during the night. This dosing regimen is 
higher than the standard dose of loperamide, but is typical for the treatment of diarrhea caused by 
anticancer therapy (Real, 2009). These doses should not be used for more than 48 hours due to 
the risk of paralytic ileus. Subjects should be provided with loperamide at the initial treatment 
visit so that they have sufficient supply on hand in case antidiarrheal support is required. It is 
important that loperamide is taken as instructed, as some cases of higher-grade diarrhea have 
occurred in subjects not taking the maximum doses, and these cases have improved after 
loperamide was taken more frequently. For subjects that cannot tolerate loperamide or do not get 
adequate relief with maximum doses, standard doses of LOMOTIL® (diphenoxylate/atropine) 
may be added or used instead of loperamide. Additional antidiarrheal measures, such as 
octreotide, may be used at the discretion of the investigator or treating physician.
2. Treat with dexamethasone
For Grade 2 or 3 diarrhea that is not adequately controlled with loperamide and dose 
interruption, administration of corticosteroid may be considered at the discretion of the treating 
physician/investigator. The subject may be treated with dexamethasone at a dose of 8 mg Q8 
hours for up to 5 days. If there still no improvement in symptoms, the subject may continue with 
the dexamethasone or consider switching to budesonide 9 mg QD. Refer to Section 6.6.2 for 
additional instructions on premedication with steroids.
If the diarrhea does not resolve to Grade 1 by 14 days, the subject will be discontinued from IP. 
If treatment interruption is longer than 28 days, the subject will be discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation).
For Grade 4 diarrhea, the subject must be discontinued from IP (refer to Section 7.2 for handing 
IP discontinuation).
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3. Interrupt AL 101 dosing
For Grade 2 or 3 diarrhea that is not controlled (i.e., to Grade 1) with loperamide, dosing of 
AL101 should be interrupted, as continued dosing is likely to result in increased severity of 
diarrhea. In addition, evaluation of infectious causes should be considered. Based on the 
mechanism of action and preliminary clinical experience, full gastrointestinal (GI) tract recovery 
will likely take longer than the time for diarrhea to resolve. Thus, interruption for 5 days to 7 
days beyond the resolution of diarrhea should be considered. Depending on the severity, time to 
onset, and time to resolution of diarrhea, reduction of AL101 dose and/or frequency, omission of 
future doses, or corticosteroid co-administration should be considered (as outlined in 
Section 6.6.2). If the diarrhea does not resolve to Grade 1 by 14 days, the subject will be 
temporarily discontinued from IP. If IP interruption is longer than 28 days, the subject will be 
permanently discontinued from IP (refer to Section 7.2 for handling IP discontinuation).
4. Increase fluid intake and, if applicable, consider stopping antihypertensive therapy 
and nonsteroidal anti-inflammatory drugs
Hypotension and/or renal insufficiency can occur in the setting of volume depletion from severe 
diarrhea. At the onset of any diarrhea, subjects should be instructed to increase fluid intake to 
help maintain fluid and electrolyte balance during episodes of diarrhea. Parenteral hydration 
should be started if oral hydration is not sufficient. The investigator should consider interrupting 
antihypertensive therapy and nonsteroidal anti-inflammatory drugs, if medically appropriate.
6.4.3.
Guidelines for the Management of Hepatotoxicity
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN 
and concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent findings are 
those that derive from a single blood draw or from separate blood draws taken within 8 days of 
each other. Follow-up investigations and inquiries will be initiated promptly by the 
investigational site to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (e.g., cholelithiasis and bile duct 
obstruction with distended gallbladder) or an agent other than the IP.
Cases where a subject shows an AST or ALT ≥3ULN and total bilirubin ≥ 2×ULN may need 
to be reported as SAEs. These cases should be reported as SAEs if, after evaluation they meet the 
criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the SAE 
criteria. IP should be permanently discontinued if they have an AE that meets the Hy’s Law 
criteria (Figure 2). Similarly, a subject must be discontinued from IP, if they have any liver 
function test that is Grade 4 or higher and does not resolve to <Grade 4 within 72 hours. Refer to 
Section 7.2 for handing IP discontinuation.
6.4.3.1.
Potential Drug-Induced Liver Injury (DILI) / Hy’s Law
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Appendix 3 Section 10.3 for 
reporting details). The criteria for identifying p-DILI events depend on whether the subject’s 
baseline liver biochemistry is normal or abnormal (see Figure 2). If the subject experience a 
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change in liver function tests that meet the Hy’s Law criteria, they must be discontinued from the 
study.
Figure 2
Algorithm for p-DILI identification and mandatory SAE reporting in 
subjects with - (i) normal baseline liver biochemistry, and (ii) abnormal 
baseline liver biochemistry.
Abnormal liver biochemistry suggestive of p-DILI or
signs/symptoms of liver disease (e.g. jaundice)
Repeat liver biochemistry within <3 days 
Normal baseline liver biochemistry
ALT or AST >3 xULN
AND
TB >2 xULN
AND
No cholestatic
or other apparent 
causes identified
Abnormal baseline liver biochemistry
ALT or AST >3 xULN
AND
>2 x screening baseline
or ALT or AST > 8 xULN
(regardless of baseline)
AND
TB >2 xULN
AND
No cholestatic or other
apparent
causes identified
p-DILI
p-DILI
AND
AND
IF repeat liver biochemistry
abnormal
AND
IF repeat liver biochemistry
abnormal
AND
The key responsibilities for investigators during p-DILI assessment include: (i) Early detection, 
medical evaluation (including the exclusion of other potential causes) and rapid laboratory 
confirmation of liver-related abnormalities, and (ii) Sponsor notification of p-DILI cases via 
SAE forms. Following the gathering and assessment of relevant clinical information the Sponsor 
is responsible for: (iii) Timely evaluation and triaging of p-DILI cases, (iv) Expedited reporting 
of p-DILI cases and (v) Expanded review of p-DILI cases including a detailed assessment of all 
available clinical information, investigations and biochemical data.
Investigators are expected to monitor ongoing routine and ad hoc hepatic laboratory test results 
to rapidly determine whether a subject meets p-DILI criteria. They are expected to promptly 
notify the Sponsor/Medial Monitor of all p-DILI cases. p-DILI cases may be identified by 
abnormal liver biochemistry values, whether or not they are accompanied by liver-related signs 
and/or symptoms. In both cases, expedited confirmation with repeat laboratory testing should 
occur within 3 business days using a Hepatic Laboratory Panel (ALT, AST, TB, AP). Any 
subject with an abnormal Hepatic Laboratory Panel that meets p-DILI criteria (see Figure 2) is a 
candidate for IP discontinuation. Any confirmed p-DILI events must be reported (along with a 
description of the clinical findings) to Sponsor as an SAE within 24 hours of confirmation.
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An extensive clinical history, examination and appropriate investigations should be obtained to 
exclude cholestatic and other apparent causes that may explain the observed abnormalities in 
liver function and/or hepatic signs and symptoms. Other apparent causes include, non-
exhaustively and by way of example only: infectious diseases (such as active hepatitis -A, -B and 
-C), congenital diseases (such as Gilbert’s syndrome), neoplastic diseases (such as hepatocellular 
carcinoma), autoimmune diseases (such as primary biliary cirrhosis) and the use of concomitant 
hepatotoxic medications (such as antibiotics, the oral contraceptive pill and herbal medicines). 
All investigations to exclude potential causes of liver function abnormalities or hepatic signs 
and/or symptoms should be guided by relevant factors such as the subject’s age, gender, clinical 
history, and signs and symptoms.
6.4.4.
Guidelines for the Management of Colitis
For management of colitis see Table 4.
Table 4
Colitis Management
Grade
Dose Modification
Management
Any Grade

Subjects should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, infections including testing for clostridium 
difficile toxin, etc.)

Steroids should be considered in the absence of clear 
alternative etiology, even for low grade events, in order to 
prevent potential progression to higher grade event
Use analgesics carefully; they can mask symptoms of perforation 
and peritonitis
Grade 1
No dose 
modification
Actively monitor frequency, consistency and appearance of stools 
(especially for presence of mucus or blood) and for the emergence 
of abdominal pain or cramps
Grade 2
If on AL101 6 mg 
QW: For first 
episode, change dose 
regimen to 6 mg 2 
weeks on / 1 week 
off
Second episode, 
decrease dose to 
4 mg QW and for 
third episode 
decrease dose to  
2.4 mg QW
If on AL101 4 mg 
QW: Decrease dose 
to 2.4 mg QW

Promptly start prednisone 1 to 2 mg/kg/day or IV equivalent

Evaluate for C.difficile and, if positive, treat with 
appropriate antibiotics

If event is not responsive within 3-5 days or worsens 
despite prednisone at 1-2 mg/kg/day or IV equivalent, GI 
consult should be obtained for consideration of further 
workup such as imaging and/or colonoscopy to confirm 
colitis and rule out perforation 

Consult Ayala Medical Monitor if no resolution to ≤ Grade 1 
in 3-4 days in order to determine whether to continue to hold 
the dose or to discontinue IP. This will depend on the overall 
clinical situation.

Therapy may only be restarted with the dose reduction upon 
resolution to ≤ Grade 1
Once improving, gradually taper steroids over ≥28 days and 
consider prophylactic antibiotics, antifungals and anti PCP 
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Grade
Dose Modification
Management
treatment (please refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B recommendation])
Grade 3-4
Permanently 
discontinue IP

Promptly initiate empiric IV methylprednisolone 2 
to 4 mg/kg/day or equivalent

Monitor stool frequency and volume and maintain hydration

Urgent GI consult and imaging and/or colonoscopy as 
appropriate

Ensure GI consult to rule out bowel perforation

Once improving, gradually taper steroids over ≥28 days or as 
appropriate and consider prophylactic antibiotics, antifungals 
and anti PCP treatment (please refer to current National 
Comprehensive Cancer Network [NCCN] guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation])
6.5.
Treatment of Overdose
Any overdose of IP should be recorded in the eCRF (including quantity of the excess dose and 
the duration of the overdose). AEs associated with an overdose or incorrect administration of IP 
should be recorded in the AE eCRF. An overdose will not be considered an SAE unless the 
outcome of the overdose meets seriousness criteria.
For this study, any dose of IP greater than the weekly dose will be considered an overdose.
In the event of an overdose, the investigator should:
1.
Contact the Sponsor’s Medical Monitor immediately.
2.
Closely monitor the subject for any AE/SAE and laboratory abnormalities until IP for at least 7 
days.
3.
Document the quantity of the excess dose as well as the duration of the overdose in the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.6.
Concomitant Therapy
Concomitant medication is defined as any prescription or over-the-counter preparation, including 
vitamins and supplements. Use of concomitant medication from 28 days before Day 1 of Cycle 1 
through 30 days after the last dose of IP must be recorded onto the eCRF from the subject’s 
medical file. This will include trade name or generic name, strength, unit, route of 
administration, dosage form, frequency, indication, start and stop date(s) of administration.
6.6.1.
Premedication to Prevent Hypersensitivity Reaction
Histamine is a major mediator of anaphylactic/anaphylactoid responses in man, such as those 
induced by Cremophor EL, an excipient in AL101. The premedication regimen below is based 
on clinical experience with other compounds containing Cremophor EL.
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In order to prevent a hypersensitivity reaction, all subjects initiating AL101 treatment will be 
premedicated approximately 1 hour prior to the infusion of AL101 with the following regimen:

H1-blocker (for example, diphenhydramine 25 to 50 mg oral or equivalent), and

H2-blocker (for example, famotidine 20 to 40 mg oral or equivalent).
For subjects who remain on study for more than 4 doses of AL101 without any evidence of 
infusion-related reaction, modification of the premedication regimen may be considered at the 
discretion of the investigator, with notification of the Sponsor’s Medical Monitor. At this time, 
1 of the 2 histamine blockers may be discontinued; if there is still no evidence of infusion-related 
reaction with the next 2 doses of AL101, the other may be discontinued. If under this 
discontinuation plan, the subject has an infusion-related reaction resulting in medical treatment, 
premedication with H1- and/or H2-blockers (as appropriate) should be resumed for subsequent 
doses.
If a subject experiences a Grade 3 or 4 infusion-related reaction despite pretreatment with the 
H1- and H2-blockers then the subject, if re-treated, should also be premedicated with 
corticosteroids (as described in Section 6.6.2) in addition to the H1- and H2-blockers). In the 
event that a subject has a repeat Grade 3 or 4 infusion-related reaction despite premedication 
with H1- and H2-blockers and steroid, the subject must not receive any further treatment with 
AL101, unless agreed by the Sponsor/Medical Monitor and investigator that it is in the subject’s 
best interest to continue treatment (e.g. subject has had a response to therapy) and appropriate 
safety measures can be implemented. Such measures may include dose reduction, increased 
infusion time, initial lower infusion rate with gradual increases, and/or premedication with 
multiple doses of dexamethasone. These measures have been used to allow re-treatment after 
infusion reactions with other agents, including IXEMPRA and Taxol (Peereboom, 1993).
6.6.2.
Premedication with Corticosteroids
All subjects will receive premedication with corticosteroids as prophylaxis utilizing the 
approximately following regimen.

8 mg dexamethasone Per Os (PO) the night before each infusion

8 mg dexamethasone PO or IV within 30 minutes prior to dosing

8 mg PO every 8 hours for an additional 4 doses starting about 4 to 8 hours after the 
infusion is finished

Repeat for the first 4 doses (first cycle).
If there are no GI toxicities following the first 4 infusions, the number of additional doses 
following the future infusions can be decreased from 4 to 2 doses of 8 mg PO every 8 hours.
Further tapering should only be considered if, in the opinion of the investigator, steroid side 
effects are an issue and after discussion with the Sponsor’s Medical Monitor.
Other steroids, such as budesonide or prednisone may be used utilizing “prednisone equivalent” 
conversions.
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6.6.3.
Allowed Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If 
changes occur during the study period, documentation of drug dosage, frequency, route, and date 
may also be included on the eCRF.
All concomitant medications received within 28 days before the first dose of IP and 30 days after 
the last dose of IP should be recorded. Concomitant medications administered after 30 days after 
the last dose of IP should be recorded for SAEs and AESIs. In addition, all prior therapies for BC 
should be recorded as specified in Section 8.2.1.
Allowed concomitant therapies:

Glucocorticoids (for instructions on premedication with corticosteroids refer to 
Section 6.6.2).

In case of toxicity (e.g., GI AEs), per discretion of the investigator and in consultation with 
the Sponsor’s Medical Monitor, dexamethasone (for example 4-8 mg every 6 hours for up to 
72 hours, starting 12 hours before AL101 administration or per institution guidelines) will be 
permitted.

Palliative radiation therapy to a limited field (e.g., painful bone metastasis, painful lumps), if 
it is not the sole site of measurable and/or assessable disease, is allowed any time during 
study participation with prior approval of the Sponsor’s Medical Monitor.
6.6.4.
Prohibited Concomitant Medication
Medications specifically prohibited in the exclusion criteria are not allowed during the ongoing 
study. If there is a clinical indication for any medication or vaccination specifically prohibited 
during the study, discontinuation from study therapy or vaccination may be required. The 
investigator should discuss any questions regarding this with the Sponsor’s Medical Monitor. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or the 
subject’s primary care physician. However, the decision to continue the subject on study therapy 
or vaccination schedule requires the mutual agreement of the investigator, the Sponsor and the 
subject.
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment periods (including retreatment for post-complete response relapse) of this study:

Prior treatment with gamma secretase inhibitors.

Exposure to any investigational drug within 4 weeks or 5 half-lives whichever is longer or 
concurrently with IP administration.

Chronic systemic glucocorticoid use (high dose defined as > 10 mg/day prednisone or 
equivalent).

Use of any herbal supplements within 1 week prior to IP administration.

Use of medications causing Torsades de Pointes within 1 week or 5 half-lives (whichever is 
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longer).

Use of strong inhibitors of CYP3A4 within 1 week or 5 half-lives (whichever is longer) or 
strong inducers of CYP3A4 within 2 weeks or 5 half-lives (whichever is longer). Refer to 
Section 10.5.
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study. Subjects may receive 
other medications that the investigator deems to be medically necessary.
The Exclusion Criteria describes other medications that are prohibited in this study.
There are no prohibited therapies during the post-treatment follow-up period.
6.7.
Intervention after the End of the Study
No formal open-label extension is planned.
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7.
DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
AND/OR STUDY
7.1.
Stopping Rules
The Simon two-stage optimal design includes pre-specified stopping rules (see Figure 1).
7.2.
Discontinuation of Investigational Product
In some instances, it may be necessary for a subject to permanently discontinue IP.
Dosing of IP must be interrupted for any serious adverse reactions assessed by the investigator as 
related to IP. Restart of dosing may be considered upon approval by the Sponsor’s Medical 
Monitor (or designee) after resolution of IP treatment-related events to baseline.
Discontinuation of IP does not represent withdrawal from the study. Subjects may withdraw or 
be withdrawn from IP at any time.
A subject may discontinue IP for reasons including but not limited to:

Adverse event

Death

Lost to follow-up

Non-compliance with study drug

Physician decision

Pregnancy

Progressive disease

Protocol deviation

Study terminated by Sponsor

Withdrawal by subject
The reason for subject discontinuation from IP will be recorded in the eCRF.
Please refer to Section 6.4 for AL101 dose modifications and toxicity management which may 
lead to IP discontinuation. Pregnancy is a mandatory criterion for permanent discontinuation of 
IP. Any subject being managed with dose interruption for toxicity should have their study 
assessments followed per SoA.
All subjects who permanently discontinued IP will undergo an End of Study visit. For subjects 
who have discontinued IP due to reasons other than disease progression, tumor assessment will 
be continued at the protocol-specified schedule until documented disease progression or 
initiation of subsequent anticancer therapy, whichever comes first. See SoA (Section 1.3) for data 
to be collected at the End of Study visit.
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7.3.
Withdrawal from the Study
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the investigator or at the institution.
A subject may withdraw from the study for reasons including but not limited to:

Death

Withdrawal by subject

Lost to follow-up

Study terminated by Sponsor
The subject will be permanently discontinued both from the IP and from the study at that time.
If the subject withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.
If the subject withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records.
If a subject is withdrawn from the study, every effort should be made to determine the reason. 
This information will be recorded on the subject’s eCRF. Subjects who withdraw from the study, 
regardless of cause, should undergo all EOS assessments as specified in Schedule of Activities 
(SoA; Section 1.3). Follow-up visits will be scheduled, per protocol.
The Sponsor reserves the right to terminate the study at any time for any reason. Such reasons 
may be any of, but not limited to, the following:

Lack of efficacy of the IP;

Occurrence of AEs unknown to date in respect of their nature, severity, and duration 
or the unexpected incidence of known AEs;

Medical, scientific, ethical, or administrative reasons affecting the continued 
performance of the study.
Regulatory Authorities also have the right to terminate the study for any reason.
7.4.
Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study.
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
Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record.

Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1).
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8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue IP.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA.
8.1.
Efficacy Assessments
Planned time points for efficacy assessments are provided in the SoA (Section 1.3).
8.1.1.
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
The primary efficacy endpoint, ORR, will be evaluated using RECIST v1.1 (Eisenhauer, 2009) 
as described in Section 10.6 (Appendix 6). A repeat of tumor imaging will be required for the 
purposes of confirmation of response (i.e., partial response, and/or complete response). The 
confirmation scan should be no earlier than 4 weeks following the first indication of response.
In addition to local imaging assessments performed by the investigator, scans will be collected 
and held for possible future retrospective independent evaluation. The investigator is responsible 
for diagnostic and treatment decisions concerning their subjects.
Disease staging will be collected at diagnosis and Screening for this protocol, prior to any 
treatment initiation. The minimum duration of stable disease will be defined as  4 weeks in 
determining the best overall response. To document evidence of prior disease progression, tumor 
measures prior to baseline assessments may be requested by the Sponsor.
The imaging requirements are provided in Table 5.
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Table 5
Imaging Guidelines
Study Period
Schedule
Imaging (RECIST 1.1)
Screening
Within 28 days prior 
to day 1
At screening, the following imaging scans are required:
1.
Brain MRI (preferred) or CT (acceptable) with contrast
2.
CT of chest
3.
CT of abdomen
4.
CT of pelvis
5.
Bone scan
Treatment
Every 8 weeks (± 3 
days) until disease 
progression
Follow-up scans at 8-week intervals, the following image scans are required:
1.
Brain MRI/CT with contrast for known or suspected disease, can be done every 12 weeks; same 
modality as screening should be used throughout the study.
2.
CT of chest
3.
CT of abdomen
4.
CT of pelvis
5.
Bone scan to be done every 16 weeks, if bone metastases at Screening
End of 
Study(EOS) 
Visit
30 days post last IP (± 
7 days)
At EOS, the following image scans are required:
1.
Brain MRI/CT with contrast for known or suspected disease; same modality throughout the study.
2.
CT of chest
3.
CT of abdomen
4.
CT of pelvis
5.
Bone scan, if indicated for known or suspected disease
Long-Term 
Follow-up
Every 3 months (± 7 
days) until disease 
progression or until 
the subject initiates 
another anti-cancer 
therapy
Only in subjects who discontinued IP due to toxicity, the following Long-Term Follow-up image scans are 
required:
1. Brain MRI/CT with contrast for known or suspected disease; same modality throughout the study.
2. CT of chest
3. CT of abdomen
4. CT of pelvis
5. Bone scan, if indicated for known or suspected disease
Confirmation 
of Response 
Scan
The confirmation scan 
should be no earlier 
than 4 weeks 
following first 
indication of response 
(PR or CR)
For confirmation no earlier than 4 weeks following a PR or CR, the following are required:
1. Brain MRI/CT with contrast for known or suspected disease; same modality throughout the study.
2. CT of chest
3. CT of abdomen
4. CT of pelvis
5. Bone scan, if indicated for known or suspected disease
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8.1.2.
Patient Reported Outcome: European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire 30 questions (EORTC 
QLQ-C30) and Breast Cancer 45 Questions (EORTC QLQ-BR45)
The EORTC QLQ-C30 and EORTC breast cancer module QLQ-BR45 will be administered 
during the study every 4 weeks before IP administration.
EORTC QLQ-C30 was developed as an instrument to measure cancer subjects’ physical, 
psychological and social functions (Kaasa, 1995). The questionnaire is composed of 5 multiitem 
scales (physical, role, social, emotional and cognitive functioning) and 9 single items (pain, 
fatigue, financial impact, appetite loss, nausea/vomiting, diarrhea, constipation, sleep disturbance 
and quality of life) (Kyriaki, 2001). It is validated and reliable and has been used successfully in 
various types of cancer, including BC (Mierzynska, 2020).
EORTC QLQ-BR23 was developed as an add-on instrument to EORTC QLQ-C30, to measure 
specifically measure breast cancer quality of life using 23 items. Recently, it was updated to 
include 45 items (EORTC QLQ-BR45) to include 23 items from the QLQ-BR23 and 22 new 
items (Bjelic-Radisic, 2018). The new items contain two multi-item scales: a target symptom 
scale and a satisfaction scale. The target symptom scale can be divided into three subscales: 
endocrine therapy, endocrine sexual and skin/mucosa scale (Bjelic-Radisic, 2020). The new 
EORTC QLQ-BR45 module that provides a more accurate and comprehensive assessment of the 
impact of new and scalable treatments on patients’ QoL.
An example of the English version of the EORTC QLQ-C30 can be found at this link:
https://www.eortc.org/app/uploads/sites/2/2018/08/Specimen-QLQ-C30-English.pdf
An example of the English version of the EORTC QLQ-BR45 can be found at this link:
https://www.eortc.org/app/uploads/sites/2/2018/08/Specimen-BR45-English.pdf
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Medical History and Prior Therapies
Any clinically significant diseases in the prior 3 years including any co-morbid conditions 
requiring active treatment as well as significant surgeries will be documented in the medical 
history section of the eCRF. This includes prior medical history and treatment regimen for 
TNBC.
Abnormal physical examination finding and/or the diagnosis of concomitant disease resulting 
from assessment at Screening must be also documented in the medical history section.
Information on all interventions (systemic therapy, surgery, radiation treatment) related to the 
subject’s cancer will also be collected. Radiology and photography reports from imaging 
conducted as routine care will be collected if available from the last 3 years.
8.2.2.
Eastern Cooperative Oncology Group (ECOG) Performance Status
The Eastern Cooperative Oncology Group (ECOG) Performance Status will be used to assess 
subjects’ performance status (Table 6).
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Table 6
ECOG Performance Status
ECOG PERFORMANCE STATUS
Grade ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
8.2.3.
Physical Examination
The complete physical examination will include appearance, eyes, ears, nose, head, throat, neck, 
lungs, heart, abdomen, extremities, skin, and musculoskeletal system.
Treatment directed physical examination, will be conducted as outlined in the SoA (Section 1.3).
Significant findings made after the start of IP which meet the definition of an AE must be 
recorded on the AE eCRF.
Height will be recorded at Screening and weight measurements using a medical scale will be 
recorded as outlined in the SoA.
Investigators should pay special attention to clinical signs related to previous serious illnesses.
8.2.4.
Vital Signs
Vital signs (to be taken before blood collection for laboratory tests) will be measured at all study 
visits and will include heart rate, respiratory rate, temperature, and blood pressure (systolic and 
diastolic). Blood pressure and heart rate will be done at rest as per standard practice at the 
investigational site. Significant findings noticed after the start of IP and findings that worsen 
significantly, which meet the definition of an AE must be recorded on the AE eCRF.
8.2.5.
Electrocardiogram
Single 12-lead ECG will be obtained and evaluated locally as specified in the SoA (Section 1.3). 
Additional timepoints may be added, as clinically indicated.
Subjects should be in the supine position after the subject has rested for at least 5 minutes. In the 
event of possible ECG findings, additional ECG reads could be added at follow-up visits. 
Clinically significant ECG abnormalities will be recorded on the eCRF.
8.2.6.
Clinical Safety Laboratory Assessments

See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed 
and to the SoA (Section 1.3) for the timing and frequency.
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The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the subject's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of IP should be repeated 
until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the Sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA 
(Section 1.3).

Laboratory values which are abnormal AND lead to either a change in dose of the IP, 
the requirement for an intervention, the requirement for additional medications, or are 
felt to otherwise be medically important should be recorded as adverse events in the 
eCRF.
8.3.
Adverse Events and Serious Adverse Events
Progression of the cancer under study is not considered an adverse event.
The definitions of an AE and  SAE can be found in Appendix 3 (Section 10.3).The definition of 
AESI can be found in Section 8.3.5.
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE, SAE, or AESI. Investigators remain 
responsible for following up AE, SAEs and other reportable safety events for outcome.
8.3.1.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information
All AEs, SAEs and other reportable safety events that occur after the consent form is signed but 
before IP administration must be reported by the investigator if the event cause the subject to be 
excluded from the study, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, or a procedure.
Table 7 below summarizes the different reporting timelines for AEs, SAEs, SUSAR, AESIs and 
pregnancy.
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Table 7
Adverse Event Reporting Timelines to the Sponsor
Type of 
Event
AE
SAE / SUSAR
AESI related to IP
Pregnancy
Reporting 
period
From consent 
until 30 days 
after last dose of 
IP
From consent until 30 
days after the last IP 
dose, and any time 
after that window if 
the SAEs are believed 
to be related to AL101
From consent until 
30 days after the last 
dose of IP, or the 
initiation of a new 
anti-cancer therapy
From consent until 
120 days after last 
dose of IP
Reporting 
Timelines 
to the 
Sponsor 
Entered into the 
clinical database 
on an ongoing 
basis 
Within 24 hours 
Within 24 hours
Within 24 hours
Reporting 
Method
AE eCRF
AE eCRF
AE eCRF
Pregnancy form in 
eCRF
Abbreviation: Adverse event (AE), adverse events of special interest (AESI), Serious adverse event (SAE), serious 
unexpected suspected adverse reaction (SUSAR)
Medical occurrences that begin before the start of IP but after obtaining informed consent will be 
recorded on the Medical History/Current Medical Conditions section of the eCRF not the AE 
section.
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, , as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the IP or study participation, the investigator must promptly notify the Sponsor.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in Section 8.3.5),
will be followed until resolution, stabilization, the event is otherwise explained, or the subject is 
lost to follow-up (as defined in Section 7.4). Further information on follow-up procedures is 
provided in Appendix 3 (Section 10.3).
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8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of 
an IP under clinical investigation are met.

The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of an IP under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent 
Ethics Committees (IEC), and investigators.

For all studies investigator safety reports must be prepared for suspected unexpected 
serious adverse reactions (SUSAR) according to local regulatory requirements and 
Sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.3.5.
Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the IP and may 
require close monitoring and rapid communication by the investigator to the Sponsor. An AESI 
may be serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of 
these events in order to characterize and understand them in association with the use of this IP. 
AESI for AL101 include events that are mediated by disruption of the Notch signaling pathway 
and can be attributed to the drug’s mechanism of action with no clear alternate etiology and 
which may require more frequent monitoring and/or interventions. All AESI must be reported in 
the AESI section of the CRFs.
AESI observed with AL101 are detailed in the sections below and include hepatic function 
abnormalities, colitis, infusion reactions (including anaphylaxis), keratoacanthoma, and hepatic 
toxicities including drug induced liver injury (DILI). For treatment of these AESIs, please refer 
to Section 6.4.
8.3.5.1.
Colitis
In study CA216001, DLTs consisting of Grade 3 colonic ulceration/Grade 3 diarrhea were 
reported, both indicating the potential for development of colitis. Intestinal inflammation is 
thought to be an on-target effect that requires close monitoring and potential dose reductions. 
Intense abdominal pain, severe diarrhea and the presence of blood and/or mucous in the stools 
are indicative of potential colitis. Signs and symptom of colitis should prompt work up to rule 
out an infectious etiology. The gold standard for the diagnosis of colitis pathological and thus 
requires a biopsy, but in the absence of an infectious etiology, colitis should be the exclusion 
diagnosis. For management of colitis see Table 4.
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8.3.5.2.
Infusion Reactions (including Anaphylaxis)
In study CA216001 1 subject developed Grade 3 anaphylaxis, a DLT at the 4 mg dose.
For infusion reactions, refer to Section 6.4.1
8.3.5.3.
Keratoacanthoma
Two cases of keratoacanthoma (a well-differentiated variant of SCC, sometimes considered 
benign) were reported with AL101 (4 mg QW):

In the BMS study CA216001, a Grade 2 keratoacanthoma (subject 3-37) was assessed as 
related AL101 and occurred 3-5 months after initiation of AL101.

In the ongoing AL-ACC-01 (ACCURACY) study, a Grade 1 keratoacanthoma (subject 
no. 1101-002), was assessed by both the investigator and the Sponsor as related to AL101 
and unexpected.
All subjects should be closely monitored for skin changes by the investigators throughout the 
study. Any changes suspicious for malignancy should be evaluated by a dermatologist and 
treated appropriately. In addition, to remove additional risk factors for developing 
keratoacanthoma, all subjects will be counseled to avoid excessive sun and UV exposure during 
the study.
8.3.5.4.
Hepatic Function Abnormalities (hepatotoxicity)
In study CA216001 a G5 (fatal) case of liver toxicity was reported at the 8.4 mg dose in the 
escalation phase of the study (refer to the Investigator’s Brochure).
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN 
and concurrent increase in total bilirubin to be greater than 2 × ULN. Concurrent findings are 
those that derive from a single blood draw or from separate blood draws taken within 8 days of 
each other. Guidelines for management of subjects with hepatic function abnormality are 
outlined in Section 6.4.3.
Cases where a subject shows an AST or ALT ≥3ULN and total bilirubin ≥ 2×ULN may need 
to be reported as SAEs. These cases should be reported as SAEs if, after evaluation they meet the 
criteria for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the SAE 
criteria. IP should be interrupted immediately if any Hy’s law cases (section 6.4.3.1). Of note, if a 
subject meets the criteria for Hy’s Law, they must be immediately discontinued from IP (refer to 
Section 7.2 for handing IP discontinuation).
8.3.6.
Disease Progression
Clinical signs or symptoms associated with progression of underlying malignancy are not 
reported as AEs if they are clearly consistent with the suspected progression of the underlying 
malignancy. Clinical symptoms of progression may be reported as AEs if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy or does not fit the 
expected pattern of progression for the disease under study. The site should report clinical 
signs/symptoms that have met the SAE definition within 24 hours of learning the event if the 
etiology is not clear at the time of the onset. If the subsequent workup has revealed that the 
reported event is associated with progression of underlying malignancy, the follow-up 
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information should be submitted, and event term should be updated to the cause that lead to the 
hospitalization instead of disease progression. For example, if a subject is hospitalized with 
shortness of breath that is determined to be associated with worsening of pleural effusion during 
the subsequent workup, pleural effusion could be used an event term instead of disease 
progression.
If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE or SAE.
8.3.7.
Death Events
All death events will require completion of a death data collection page within the eCRF.
Timelines for reporting of death events are identical to the requirements for SAE reporting. 
Events resulting in death will be an SAE regardless of association to disease progression 
(Section 10.3.5). Death is an outcome and should not be reported as an event term. The event that 
lead to the death should be reported as the SAE term.
8.3.8.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects will 
be collected as outlined in Appendix 4 (Section 10.4).

If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4).

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.4.
Biomarkers and Pharmacokinetics
8.4.1.
Activating Notch Alteration Detection by NGS Assay
The planned use of a commercially available NGS assay, LDT or other validated IUO clinical 
trial assay capable of detecting activating genetic alterations in the NOTCH 1/2/3/4 genes is to 
identify for inclusion those subjects most likely to benefit from therapy with AL101.
Notch mutational status from prior tests with commercially available or LDT NGS assay as 
assessed at enrollment may be confirmed centrally. In the US, any FDA-cleared/approved, 
validated CTA, or LDT NGS assay is acceptable. In Europe any commercially available CE 
marked device can be used.
For questions, please contact the Sponsor’s Medical Monitor.
8.4.2.
Pharmacokinetics
Blood samples for PK will be obtained at the times designated in the SoA, footnote p (Table 1). 
Start- and end-time for each investigational product infusion (and any interruptions) will be 
recorded in the eCRF. In addition, the actual time of the sample collection will be recorded in the 
eCRF. All samples will be analyzed for both parent and metabolite using liquid chromatography 
with tandem mass spectrometry (LC-MS/MS) assay.
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Analysis will be conducted to assess the PK characteristics of AL101 at the first dose and at 
steady state, and to determine whether any of the following covariates — age, body size, sex, 
organ impairment, drug-drug interaction — influence the PK of AL101.
For more details on instructions for collecting PK samples, refer to the Study Laboratory 
Manual.
8.4.3.
Other Biomarkers
Predictive biomarkers of response or resistance to the IP will be explored, such as but not limited 
to:

IHC: Tumor specimens will be stained for the NICD and potentially other 
biomarkers.

NGS: Mutational analysis will be performed in tumor tissue samples and potentially 
in blood (cfDNA, CTCs).
Biomarkers indicative of drug activity may be explored, such as but not limited to:

CTC enumeration.

Expression of pharmacodynamic biomarkers of Notch inhibition in tumor tissue 
and/or CTCs.
Samples may be stored according to local regulations following the last subject’s last visit for the 
study at a facility selected by the Sponsor to enable further analysis of biomarker responses to 
AL101.
8.4.4.
Sample Collection
Tumor tissue and blood will be collected at the times designated in the SoA (Section 1.3). 
Any biopsy should not exceed the risk associated with a simple excisional, incisional or core 
biopsy. Tumor tissue for biomarker analysis will be required for study participation at screening 
(block or 25 unstained slides). Tumor biopsies will also be taken at Cycle 4 Day 1 ±28 days. 
Screening biopsies may be fresh, or archival from within 2 years. On-treatment biopsies do not 
need to be done if either the site investigator or person performing the biopsy judges that no 
tumor is accessible for biopsy or that biopsy poses too great of a risk to the subject. (If the only 
tumor accessible for biopsy is also the only lesion that can be used for RECIST v1.1 response 
evaluation, then the subject may be exempt from biopsy after discussion with the Sponsor).
The Laboratory Manual will provide details on biomarker sample collection.
8.5.
Genetics
Germline genetics are not evaluated in this study.
8.6.
Unscheduled Visits
There may be a need to have a subject return to clinic for an unscheduled visit for a variety of 
reasons, including but not limited to repeat of a lab test, evaluation of an AE, or evaluation of 
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disease status. Any procedure that is conducted during a regularly scheduled on-treatment visit 
may be performed at an unscheduled visit and will be recorded in the eCRF.
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9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypothesis and Sample Size Determination
The study will utilize the Simon two-stage optimal design (Figure 1 and Table 8) and will 
include up to 67 to 73 subjects, depending on IP dose evaluated in Stage 1 and Stage 2 as 
follows:

if the AL101 dose is 6 mg QW throughout the study, there will be up to 67 subjects 
evaluated, including the 6 subjects in the lead-in cohort for the Stage 1 evaluation.

if AL101 4 mg is evaluated in Stage 1 and Stage 2, there will up to 73 enrolled 
subjects consisting of up to 67 subjects at AL101 4 mg and 6 subjects in the lead-in 
cohort of AL101 6 mg. Note, the lead-in cohort will not be included in the Stage 1 
evaluation.
In both scenarios there will be up to 26 evaluable subjects in Stage 1, and 41 additional evaluable 
subjects in Stage 2 provided at least 4 subjects (out of 26) responded in Stage 1.
While the data on Stage 1 is maturing, Stage 2 will continue enrolling an additional 41 subjects, 
unless an unexpected safety signal emerges that in the judgement of the DMC requires analysis 
and/or poses a serious threat to the well-being of the subject. This decision will be made in 
agreement with the Sponsor. 
If no more than 3 subjects respond in Stage 1, the study will be stopped for futility. If 4 or more 
subjects respond, Stage 1 will be considered positive. For the entire study (Stages 1 and 2), the 
null hypothesis will be rejected if 15 or more responses are observed in 67 subjects. Only the 
Efficacy Evaluable set of subjects will be counted toward this analysis. This design has 80% 
power at the 5% type I error level to detect a desirable success rate of 23% against the null 
hypothesis of an unacceptable success rate of 11%. The success rate parameters for the two-stage 
design are aligned with recent published experience of clinical studies (Twelves, 2014). If at the 
end of Stage 1, there are 4 responses in the Notch-activated TNBC subjects, the study will 
continue to Stage 2.
Table 8
Sample Size Hypothesis
Total
Look1
Expected
Sample 
Size
Sample 
Size
Futility Boundary
Attained
Attained
Probability of
Sample Size
(n)
(n_1)
Look1
Look2
Alpha
Power
Early
H0 (EN0)
(r_1)
(r_2)
Stopping
67
26
3
11
0.049
0.807
0.681
39.1
9.2.
Analysis Populations
The following analysis sets will be used in this study:

Safety analysis population: All subjects who receive at least one dose of IP (even a 
partial dose).
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Efficacy evaluable population: All subjects who receive at least one dose of IP at the 
dose as determined by the lead-in cohort, have measurable disease at baseline per 
RECIST v1.1, and have at least one post-baseline on-study assessment of tumor 
response, unless there is documented clinical progression after discussion with 
Sponsor’s Medical Monitor or radiological progression prior to Week 8.

Per-protocol (PP) analysis population: All efficacy evaluable subjects who have no 
major protocol violations, as defined by the Sponsor prior to database lock.
Note: if there is a discrepancy between the Notch-activated mutation determination between 
commercial/LDT NGS assay and the confirmatory central assay, the subject will be non-
evaluable for the Efficacy and PP evaluations.
9.3.
Statistical Analyses
The statistical analysis plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints.
The standard summary statistics for continuous variables are sample size (n), mean, standard 
deviation, median, minimum and maximum. The standard summary statistics for categorical 
variables are frequencies and percentages. Time to event variables will be summarized using the 
Kaplan-Meier method. Where confidence limits are appropriate, the confidence level will be 
95% (two-sided), unless otherwise stated. The only test of statistical significance will be 
performed according to the pre-defined analysis of the Simon two-stage optimal design.
Individual data (including relevant derived variables) will be presented by parameter in listings. 
Results of statistical analyses, descriptive summary statistics and supportive listings will also be 
presented.
Baseline values are defined as the last valid value prior to IP administration. Baseline safety data 
will be presented along with subsequent safety values assessed during or after drug 
administration.
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be maintained by the Sponsor. 
This document may modify the plans outlined in the protocol; however, any major modifications 
will also be reflected in a protocol amendment.
Statistical analyses will be performed using SAS® v9.4 or higher (SAS Institute, Cary NC, 
USA).
9.3.1.
Subject Disposition
The number and percentage of subjects who are enrolled, treated, discontinued from IP, and 
participating in follow-up will be presented for the Safety analysis and the Efficacy Evaluable 
population. A summary of reasons for discontinuation from treatment and withdrawal from the 
study will be provided. The number of subjects included in each analysis set will be summarized 
and the reasons for excluding subjects from each population will be listed.
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9.3.2.
Demographic and Baseline Characteristics
Demographic characteristics including age, gender, race, and ethnicity will be presented in the 
form of tabular summary statistics for all subjects in all of the above populations. Other subject 
baseline characteristics including weight, height, body mass index (BMI), initial stage of disease, 
and performance status will be presented similarly.
9.3.3.
Efficacy
9.3.3.1.
Definitions of Efficacy Endpoints
Primary: ORR, defined as the proportion of subjects who have a best overall response (BOR) of 
CR or PR as determined using RECIST v1.1. BOR is defined as the best response recorded 
between the date of first dose of IP and the date of subsequent anti-cancer therapy. A BOR of CR 
or PR requires confirmation of the assessment no earlier than 4 weeks later.
Other efficacy endpoints are as follows:

Progression free is defined as the interval from the start of study treatment to the 
earlier of the first documentation of disease progression or death from any cause.

Clinical Benefit Response is defined as SD+PR+CR.

DOR, defined as the interval from the first documentation of CR or PR to the earlier 
of the first documentation of disease progression (per RECIST v1.1) or death from 
any cause.

OS, defined as the time from the date of start of treatment to the date of death from 
any cause. Subjects who are lost to follow-up and those not known to have died by 
the cut-off date for analysis will be censored on the date the subject was last known 
alive, or the data cut-off date, whichever is earlier.
9.3.3.2.
Analysis of Efficacy Endpoints
For primary and secondary endpoints refer to Section 1.2.
The primary efficacy endpoint is the ORR based on the proportion of subjects with an overall 
response of either CR or PR. Disease response will be assessed using RECIST v1.1. Primary 
efficacy analysis will be performed on the Efficacy Evaluable population.
Secondary endpoints include CBR, DOR, PFS, PFS at 6 months, and OS. Secondary efficacy 
analysis will be performed on the Efficacy Evaluable population and Per Protocol population.
Efficacy endpoints will also be analyzed for each of the sub-populations: TNBC subjects as well 
as non-TNBC subjects.
9.3.4.
Safety and Tolerability Analysis
All safety analyses will be made on the Safety Analysis population.
The safety assessment will be based on the frequency of AEs, the incidence of clinically 
significant abnormalities of laboratory values, concomitant medication use, vital signs, pain 
assessment and physical examination data.
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Adverse events: The AE verbatim descriptions (investigator terms from the eCRF) will be 
classified into standardized medical terminology using the Medical Dictionary for Regulatory 
Activities (MedDRA). AEs will be considered treatment-emergent if they start on or any time 
after the first dose of IP until 30 days after the last dose of IP. The incidence of treatment-
emergent AEs will be summarized overall, by system organ class and preferred terms, and by 
severity grade and relationship to IP. SAEs and AEs leading to discontinuation will also be 
tabulated.
Other safety data: These data will be summarized by presenting the proportions of subjects with 
clinically significant abnormalities or by changes from baseline values. Laboratory parameters 
will be categorized according to CTCAE v5.0 grade and shifts from baseline CTCAE grade to 
worst postbaseline grade will be summarized using shift tables. Percentages will be based on the 
number of subjects with baseline and at least 1 post baseline assessment. Laboratory data will be 
listed, and abnormal results will be flagged.
9.4.
Interim Analyses
Because a Simon two-stage optimal design will be employed, ORR will be assessed during Stage 
1 for subjects who have received IP for at least 2 cycles (8 weeks) and no more than 8 cycles (8 
months). While the data on Stage 1 is maturing, Stage 2 will continue enrolling an additional 41 
subjects for a total of 67 subjects, unless an unexpected safety signal emerges that in the 
judgement of the DMC requires analysis and/or poses a serious threat to the well-being of the 
subject.
The Statistical Analysis Plan will describe the planned analyses in greater detail.
9.5.
Data Monitoring Committee (DMC)
An independent Data Monitoring Committee (DMC) will be assigned by the Sponsor prior to the 
beginning of the study. Throughout the study, the DMC will monitor safety parameters at regular 
intervals (approximately quarterly) after at least 3 subjects have been treated for at least 2 cycles 
(after the first on-treatment radiographic assessment) and then periodically as specified in the 
DMC charter. Efficacy data will also be provided to the DMC to allow assessment of benefit/risk 
for subjects. The DMC may recommend stopping the study if at any time during the study there 
are unacceptable AEs or safety concerns as described in the protocol stopping rules defined in 
the DMC charter.
For each DMC meeting, pre-specified reports will be provided. In addition, the DMC Chair will 
be provided with or have access to periodical safety and efficacy reports as specified in the DMC 
charter. The DMC Chair may share these reports with the DMC or convene additional meetings 
of the DMC at his/her discretion. The DMC Chair may request additional safety and efficacy 
data based on the review of study data.
Further details regarding data safety monitoring guidelines will be included in the DMC Charter, 
which is the governing document that supersedes this section of the protocol.
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Ethical Aspects
The Sponsor, contract research organization (CRO), and the Investigator must comply with all 
instructions, regulations, and agreements in this protocol and applicable ICH and GCP guidelines 
and conduct the study according to local regulations. The Investigator may delegate 
responsibilities for study-related tasks where appropriate to individuals sufficiently qualified by 
education, training, and experience, in accordance with applicable ICH and GCP guidelines. The 
Investigator should maintain a list of the appropriately qualified persons to whom significant 
study-related duties have been delegated. The Investigator is responsible for supervising those 
individuals and for implementing procedures to ensure the integrity of the tasks performed and 
any data generated.
10.1.1.1.
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) and 
Regulatory Authorities
Before initiation of the study at each study site, the protocol, the ICF, other written material 
given to the subjects, and any other relevant study documentation will be submitted to the 
appropriate IEC/IRB. Written approval of the study and all relevant study information must be 
obtained before the study center can be initiated or the investigational product is released to the 
Investigator. Any necessary extensions or renewals of IEC/IRB approval must be obtained for 
changes to the study such as amendments to the protocol, the ICF or other study documentation. 
The written approval of the EC/IRB together with the approved ICF must be filed in the study 
files.
It is the responsibility of the Sponsor to obtain and maintain independent approval from the 
applicable Regulatory Authorities to conduct the study in accordance with applicable regulatory 
requirements. It is the responsibility of the Sponsor to ensure that a positive opinion from the 
IEC/IRBs to conduct the study in accordance with applicable regulatory requirements is in place.
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the beginning 
of the study. On completion of the study, the regulatory authorities will be notified that the study 
has ended.
10.1.1.2.
Declaration of Helsinki/Good Clinical Practice
The Declaration of Helsinki is the accepted basis for clinical study ethics and must be fully 
followed and respected by all engaged in research on human beings. Any exceptions must be 
justified and stated in the protocol. The latest version of the Declaration of Helsinki is available 
under http://www.wma.net/en/30publications/10policies/b3/index.html.pdf. Additionally, the 
Investigator(s) and all parties involved in this study should conduct the study in adherence to the 
ethical principles based on the Declaration of Helsinki, ICH-GCP guidelines, and the applicable 
national and local laws and regulatory requirements.
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10.1.1.3.
Subject Information and Informed Consent
It is the responsibility of the Investigator to obtain written informed consent from each subject 
participating in this study, after adequate explanation of aim, importance, anticipated benefits, 
and potential hazards and consequences of the study according to applicable local laws. Written 
informed consent must be obtained before any study-specific procedures are performed. It must 
be also explained to the subject that he/she is completely free to refuse to enter the study or to 
withdraw from it at any time for any reason without incurring any penalty or withholding of 
treatment on the part of the Investigator.
With the declaration of consent the subject agrees that data on his/her medical history are 
recorded within the framework of the clinical study and that they are transferred to the Sponsor 
in a pseudo-anonymized manner. Subjects will be informed that their race and ethnicity will be 
collected and will be used during analysis of study results.
The subject also agrees to allow the monitor/auditor/health authorities to verify the collected 
subject data against the subject's original medical records for the purpose of source data 
verification.
The ICF – personally signed and dated by the subject and the Investigator – must be kept in the 
Investigator’s study file by the Investigator(s) and documented in the eCRF and the subject’s 
medical records. The Investigator confirms to the Sponsor to obtain the written informed consent 
from any subject before participating in the study.
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study, a new ICF will be approved by the EC(s)/IRB(s) (and 
regulatory authorities, if required). If new safety information results in significant changes in the 
risk/benefit assessment, the consent form should be reviewed and updated if necessary. All 
subjects (including those already being treated) should be informed of the new information and 
must give their written informed consent to continue in the study.
If the family doctors are informed of their subjects’ participation in the clinical study, this should 
be mentioned in the consent form.
10.1.1.4.
Personal Data Protection
The study will be conducted in accordance with the data protection laws that apply in a particular 
country and jurisdiction.
The Sponsor complies with the principle of subject’s right to protection against invasion of 
privacy. Throughout this study, all subject data will be identified only by a subject identification 
number. The personal data will be blinded in all data analyses. The subject must be informed and 
consent as required that authorized personnel of the Sponsor such as study monitor, auditor etc. 
and relevant health regulatory agency will have direct access to personal medical data to assure a 
high-quality standard of the study.
At the subject's request, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. Personal physician will be 
notified by site personnel of subject participation in the study.
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Monitors, auditors, and other authorized agents of the Sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the US FDA, as well as that of any other applicable 
agency(ies), will be granted direct access to the study subjects’ original medical records for 
verification of clinical study procedures and/or data, without violating the confidentiality of the 
subjects to the extent permitted by the law and regulations. In any presentations of the results of 
this study or in publications, the subjects’ identity will remain confidential.
All personal data collected and processed for the purposes of this study should be managed by 
the Investigator and his/her staff with adequate precautions to ensure confidentiality of those 
data, and in accordance with the Health Insurance Portability and Accountability Act [US 
Department of Health and Human Services. The Health Insurance Portability and Accountability 
Act (HIPAA) of 1996 (P.L.104-191) [HIPAA]. http://aspe.hhs.gov/admnsimp/pl104191.htm. 
Effective August 21, 1996.], applicable to national and/or local laws and regulations on personal 
data protection.
10.1.1.5.
Audits and Inspections
The study may be audited according to the Sponsor's quality assurance inspection program. The 
purpose of the audit is to determine whether or not the study is being conducted and monitored in 
compliance with study protocol and ICH-GCP guideline. Audit visit(s) will be arranged in 
advance with site personnel at a mutually acceptable time.
The Investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Sponsor quality assurance or its designees 
or to regulatory authority inspectors after appropriate notification. The verification of the eCRF 
data must be by direct inspection of source documents. These audits or inspections may take 
place at any time, during or after the study, and are based on the national regulations, as well as 
ICH-GCP guidelines.
10.1.1.6.
Data Quality Assurance
All subject data relating to the study will be recorded on printed or electronic case report form 
(eCRF) unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring), are provided in the Monitoring Plan.
The sponsor is responsible for the data management of this study, including quality-checking of 
the data.
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The investigator assumes accountability for actions delegated to other individuals (e.g., contract 
research organizations).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator per ICH GCP* and local regulations or institutional policies.
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written notification 
to the Sponsor.
* As per ICH E6 (R2), paragraph 1.65, computerized systems used to record data, should be validated and compliant 
with 21CFR part 11 (EudraLex4 annex 11 in EU). Data integrity should be maintained throughout the study (as per 
ICH E6 (R2) 5.5.3, Good Documentation Practiced as per ICH E6 (R2) 4.9.0 (ALCOA++).
10.1.2.
Study Monitoring
The Monitor has the responsibility to familiarize the Investigator(s) and the entire center staff 
involved in the study with all study procedures including the administration of investigational 
product. The Monitor will monitor the study conduct, proper eCRF and source documentation 
completion and retention, and accurate investigational product accountability. To this end, the 
Monitor will visit the clinical site at suitable intervals and be in frequent contact through verbal 
and written communication. It is essential that the Study Monitor has access to all documents 
(related to the study and the individual participants) at any time these are requested. In turn, the 
Monitor will adhere to all requirements for subject confidentiality as outlined in the ICF. The 
Investigator and Investigator’s staff will be expected to cooperate with the Study Monitor, permit 
the monitor, the IEC/IRB, the Sponsor’s internal auditors, and representatives from regulatory 
authorities direct access to all study-related documents and pertinent hospital or medical records 
for confirmation of data contained within the eCRFs to be available during a portion of the 
monitoring visit to answer questions, and to provide any missing information.
10.1.3.
Study Documentation
Study documentation will follow Good Documentation Practice as per ICH E6 (R2) 4.9.
Study documents will include but not be limited to the following:

Signed ICFs

Source documents (e.g., subject files, medical notes, study worksheets)

Investigator copies of the eCRFs and SAE reports

Investigator site file and contents

Study Manuals (including laboratory manual, pharmacy manuals and reference 
manual)

Investigator meeting binder and or other training materials
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Upon completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate period.
10.1.3.1.
Change in Protocol
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator.
There will be no alterations in the protocol affecting subject safety without the express written 
approval of the Sponsor, Investigator, and the IEC/IRBs.
All protocol amendments must be submitted to the EC/IRBs and regulatory authorities if 
required by local law. Protocol modifications that affect subject safety, the investigational scope, 
or the scientific quality of the study must be approved by the IEC/IRBs before implementation of 
such modifications to the conduct of the study. If required by local law, such modifications must 
also be approved by the appropriate regulatory agency before implementation. However, the 
Sponsor may, at any time, amend this protocol to eliminate an apparent immediate hazard to a 
subject. In this case, the appropriate regulatory authorities will be notified subsequent to the 
modification.
10.1.3.2.
Site Initiation Visit/Investigator Meeting
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with the 
Investigator and appropriate clinical staff to familiarize the Investigator and clinical staff with 
the clinical protocol and the materials necessary for conducting the clinical study.
10.1.3.3.
Source Document
The Investigator will permit study-related monitoring, audits by or on behalf of the Sponsor, 
IRB/IEC review and regulatory inspections providing direct access to source data documents. 
Source documents are original records in which raw data are first recorded. These may be 
office/clinic/hospital records, charts, diaries, ultrasound images, and laboratory results, ECG 
printouts, pharmacy records, care records, completed scales for each study participant and/or 
worksheets provided by the Sponsor. Source documents should be kept in a secure and limited 
access area. All source documents should be accurate, clear, unambiguous, permanent and 
capable of being audited. They should be made using a permanent form of recording (ink, typing, 
printing, optical disc, etc.). They should not be obscured by correcting fluid or have temporary 
attachments (such as removable self-stick notes). Source documents that are computer generated 
and stored electronically must be printed, signed and dated by the Investigator.
Source data for subjects registered to the study should indicate date ICF was signed, participation 
in clinical protocol number and title, treatment number, evidence that inclusion/exclusion criteria 
have been met.
10.1.3.4.
Recording of Data on Electronic Case Report Form (eCRF)
No data will be directly entered into the eCRF without source documentation.
The study worksheets provided by the Sponsor may be used to capture all study data not 
recorded in the subject’s medical record. Alternatively, the site may create and use their own 
study worksheets. Only a subject identification number will be used to identify the subject. The 
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Investigator must keep a separate log of subject names and medical record numbers (or other 
personal identifiers).
The protocol will use an Internet-Based Remote Data Entry System, primarily to collect clinical 
study data at the investigational sites. The system will be used to enter, modify, maintain, 
archive, retrieve, and transmit data. The system was configured based on requirements from the 
Sponsor. Paper source documents are to be retained to enable a reconstruction and evaluation of 
the study. No original observations will be entered directly into the computerized system. Source 
documents include the clinic or hospital subject files and study worksheets provided by the 
Sponsor. Data will be recorded in the study worksheets as appropriate to complete and/or clarify 
source data.
The design of a computerized system complies with all applicable regulatory requirements for 
record keeping and record retention in clinical studies (21 CFR Part 11 and ICH-GCP; E6) to the 
same degree of confidence as is provided with paper systems. Clinical Investigators must retain 
either the original or a copy of all source documents sent to a Sponsor or CRO, including query 
resolution correspondence. The system is designed so that changes to any record do not obscure 
the original information. The audit record clearly indicates that a change was made and clearly 
provides a means to locate and read the prior information. All changes to the data have an 
electronic audit trail, in accordance with 21 CFR 11.10(e). Electronic signatures will be used in 
conformance with 21 CFR Part 11.
10.1.3.5.
Investigator Site File
All documents required for the conduct of the study as specified in the ICH-GCP guidelines will 
be maintained by the Investigator in an orderly manner and made available for monitoring and/or 
auditing by the Sponsor or Sponsor delegate and regulatory agencies.
10.1.3.6.
Clinical Study Supplies
The Sponsor or its vendors will be responsible for providing study supplies and for ensuring that 
they are used, managed and accounted for properly. Accurate and timely records of the 
disposition and accountability of all investigational products must be maintained by the site and 
reviewed by the Sponsor representative monitor. The supplies and inventory record must be 
made available for inspection upon request. Upon completion or termination of the study, the 
Investigator will keep the remaining clinical supplies along with a copy of the inventory record 
and a record of the clinical supplies returned. Under no circumstances will the Investigator allow 
the investigational products to be used other than as directed by this protocol.
Upon completion or termination of the study, all study supplies will be disposed of per 
instructions from the Sponsor and/or its vendors (CRO).
Clinical study supplies include, however, not limited to: eCRF, study worksheets, laboratory 
supplies and investigational products.
10.1.4.
Data Management
Data Management services will be provided by the CRO. After the data have been entered and 
verified, various edit checks will be performed for the purpose of ensuring the accuracy, 
integrity, and validity of the database.
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Queries generated from these checks will be sent to the investigational site for resolution, and the 
database will be updated to reflect query resolutions as appropriate.
For details on data management processes, please refer to the Study Data Management Plan.
10.1.5.
Study Completion
This study is expected to end when all required subjects have been enrolled and the last subject 
has completed the follow-up visit of the study (30 days post last dose of investigational product) 
and query resolution has been completed. Collection of overall survival data will continue 
beyond the follow-up visit and will be reported separately from the clinical study report.
10.1.6.
Clinical Study Report
A clinical study report will be developed by the Sponsor at completion of data analysis. This 
report will be a clinical and statistical integrated report, according to the ICH E3 guidelines.
10.1.7.
Disclosure
All information provided regarding the study, as well as all information collected/documented 
during the study, will be regarded as confidential. The Investigator (or designee) agrees not to 
disclose such information in any way without prior written permission from the Sponsor.
Any publication of the results, either in part or in total (e.g., articles in journals or newspapers, 
oral presentations, abstracts) by the Investigator or their representative(s), shall require prior 
notification and review, within a reasonable time frame, by the Sponsor, and cannot be made in 
violation of the Sponsor’s confidentiality restrictions or to the detriment of the Sponsor’s 
intellectual property rights.
Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.
10.1.8.
Records
Data collected at Screening and during the study will be recorded in the subject’s source 
documents and retained at the study site for all subjects who sign informed consent. Subjects 
who are enrolled in the study will have their data retained in the source documents at the site and 
also have their data entered into the eCRF. To maintain confidentiality, subjects will be 
identified only by screening and subject numbers.
The completed eCRFs will be transferred to the Sponsor (or designee). Copies of each source 
document will be retained by the Investigator (or designee). A compact disk containing the site 
eCRF data will be provided to the site at the completion of the study. All source documents, 
records, and reports will be retained by the clinical site in accordance with 21 CFR 312.62(c). 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations. Prior to proceeding with destruction of records, the Investigator must notify the 
Sponsor in writing and receive written authorization from the Sponsor to destroy study records.
In addition, the Investigator must notify the Sponsor of any changes in the archival arrangements 
including but not limited to archival at an offsite facility or transfer of ownership if the 
Investigator leaves the site.
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All primary data, or copies thereof (e.g., laboratory records, eCRFs, data sheets, correspondence, 
photographs, and computer records), which are a result of the original observations and activities 
of the study and are necessary for the reconstruction and evaluation of any study report, will be 
retained in the clinical site archives.
10.1.9.
Financing and Insurance
Financing and insurance of this study will be outlined in a separate agreement between CRO and 
the Sponsor.
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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 9 will be performed by the local laboratory.

All safety laboratories, hematology, chemistry and urine analysis are to be drawn by 
standard phlebotomy techniques, into the site prescribed appropriate tubes for the 
specific tests and amounts prescribed by local laboratory, e.g., CBC with differential 
5 ml in a purple top tube., chemistry 10 ml in a red top tube. Refer to the laboratory 
manual for further details on specimen collection and handling procedures.

Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Investigators must document their review of each laboratory safety report.
Table 9
Protocol-Required Safety Laboratory Assessments
Hematology
White blood cell count (WBC) with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils)
Red blood cell (RBC) with indices (MCV and MCH)
Hematocrit, hemoglobin and platelet count
Serum Chemistry
Glucose, blood Urea Nitrogen (BUN), creatinine, total bilirubin, albumin, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase, lactate dehydrogenase (LDH), glucose, and electrolytes 
(sodium, potassium, chloride, calcium, magnesium, and phosphorus).
A direct bilirubin should be obtained if the total bilirubin level is >1.5 times 
ULN. Creatinine clearance will be done at Screening only.
Lipid panel
triglycerides, total cholesterol, low-density lipoprotein (LDL), and high 
density lipoprotein (HDL)
Urinalysis (dipstick)
pH, glucose, ketones, protein, specific gravity, bilirubin and evidence of 
infection; microscopic examination will be done when findings are abnormal.
Other laboratory 
assessments
Glycated hemoglobin (HbA1c)
Thyroid function: Thyroid stimulating hormone (TSH), total T3 and free T4
Coagulation assessment, including prothrombin time (PT), and activated 
partial thromboplastin time (aPTT).
Human chorionic gonadotropin (hCG) pregnancy test (as needed for women 
of childbearing potential)
Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only)
Lipase – only for subjects who experience ≥ Grade 2 diarrhea
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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a subject or clinical study subject, 
temporally associated with the use of the IP, whether or not considered related to 
the IP.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of the IP.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition other than the 
disease under study including either an increase in frequency and/or intensity of the 
condition.

New conditions detected or diagnosed after IP administration even though it may 
have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either IP or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless 
it is an intentional overdose taken with possible suicidal/self-harming intent. Such 
overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition

Clinical signs or symptoms associated with progression of underlying malignancy 
are not reported as adverse events if they are clearly consistent with the suspected 
progression of the underlying cancer, see section 8.3 Medical or surgical procedure 
(e.g., endoscopy, appendectomy): the condition that leads to the procedure is the 
AE.
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Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
A SAE is defined as any AE occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the subject has been detained for 24 hours or greater at 
the hospital or emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
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A SAE is defined as any AE occurrence that, at any dose:
above definition, such as Grade 3 or 4 infusion reactions. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
10.3.3.
Definition of Suspected and Unsuspected Adverse Reaction
Suspected adverse reactions are defined as:

Any AE for which there is a reasonable possibility that the IP caused the AE. For 
the purposes of Sponsor regulatory safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the IP and the AE. A 
suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any AE caused by IP
Unexpected Adverse events are defined as:

AE which is not listed in the Investigator’s Brochure or approved label of the IP or 
is not listed at the specificity or severity that has been observed
10.3.4.
Recording and Follow-up of AEs and SAEs
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE/AE of Interest information in 
the eCRF.

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to the Sponsor in lieu of completion of the AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all subject identifiers, with the exception of 
the subject number, will be redacted on the copies of the medical records before 
submission to the Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
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Assessment of Intensity
AE severity will be evaluated by the investigator in accordance with the NCI CTCAE v5.0 2. 
For AEs that are not adequately addressed in the NCI CTCAE, the investigator should classify 
the intensity of the AE using the following guidelines:

Grade 1: Mild: Aware of sign or symptom, but easily tolerated; no intervention 
needed

Grade 2: Moderate: Discomfort enough to cause interference with usual activity, 
minimal non-invasive intervention indicated (e.g., short course of antibiotics)

Grade 3: Severe: Medically significant but not immediately life-threatening; 
incapacitation with inability to work or do usual activity

Grade 4: Life-threatening: Refers to an event in which the subject was at risk of 
death at the time of the event, as judged by the investigator; urgent/emergent 
intervention indicated. This category should not be used for an event that 
hypothetically might have caused death if it were more severe.

Grade 5: Fatal outcome.
It will be left to the investigator’s clinical judgment to determine whether an AE is of 
sufficient severity to require the subject’s removal from treatment or from the study. A subject 
may also voluntarily withdraw consent from treatment due to what she/he perceives as an 
intolerable AE. If either of these situations arises, the subject should be strongly encouraged to 
undergo an end-of-study assessment and be under medical supervision until symptoms cease 
or the condition becomes stable. An event is defined as ‘serious’ when it meets at least 1 of the 
predefined outcomes as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between each of the study 
drugs separately and each occurrence of each AE/SAE.

Related – The AE is known to occur with the IP, there is a reasonable 
possibility that the IP caused the AE, or there is a temporal relationship 
between the IP and event. Reasonable possibility means that there is evidence 
to suggest a causal relationship between the IP and the AE.
2 Please refer to the CTCAE v5 at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference
_5x7.pdf. 
Accessed April 19, 2019
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Not Related – There is not a reasonable possibility that the administration of 
the IP caused the event, there is no temporal relationship between the IP and 
event onset, or an alternate etiology has been established.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as disease progression/underlying disease(s), concomitant 
therapy, and other risk factors, as well as the temporal relationship of the event to 
IP administration will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is 
very important that the investigator always assess causality for every event 
before the initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the Sponsor with a copy of any post-mortem 
findings including histopathology if an autopsy is performed.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours 
of receipt of the information.
10.3.5.
Reporting of SAEs and SUSAR
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The Investigator is responsible for identifying, documenting, evaluating and reporting SAEs and 
SUSARs in accordance with the protocol, 21CFR312.32, 21CFR312.64, ICH-GCP guidelines, 
and all other applicable regulations.
SAE and SUSAR Reporting to the Sponsor via an Electronic Data Collection Tool

The mechanism for reporting an SAE to the Sponsor will be the electronic data 
capture system.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information via contact to the Medical 
Monitor.

If the electronic system is unavailable, then within 24 hours, the site will contact 
the Medical Monitor to report the event or email or fax the SAE form as detailed 
below.

Contacts for SAE can be found in the Study Reference Manual.
Ayala’s Central Safety Mailbox
Precision Safety
mailto:Worldwide.Safety@ayalapharma.com
Safety Hotline fax: +1 760 683 6433
Email: 
PFM_Safety@precisionformedicine.com
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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of IP, additional evaluation should be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the subject’s medical 
records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
o
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement   is required.

Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Guidance
AL101 may have adverse effects on a fetus in utero. Furthermore, it is not known if AL101 has 
transient AEs on the composition of sperm. Non-pregnant, non-breast-feeding women may be 
enrolled if they are willing to use a high effective method of birth control or are considered 
highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically sterilized, or 
2) postmenopausal (a woman who has not had menses for greater than 1 year will be considered 
postmenopausal), or 3) not heterosexually active for the duration of the study. Subjects should 
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start using birth control for 30 days prior to treatment initiation (Cycle 1, Day 1) and throughout 
the study period up to 120 days after the last dose of IP.
The following are considered highly effective method of contraception:
For women of childbearing potential, including female study subjects and partners of male 
subjects, effective contraception is defined as follows:

combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
-
oral
-
intravaginal
-
transdermal

progestogen-only hormonal contraception associated with inhibition of ovulation:
-
oral
-
injectable
-
implantable

intrauterine device (IUD)

intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion

vasectomized partner with documentation of the success of the vasectomy

complete abstinence from heterosexual intercourse (periodic abstinence is not a safe 
method)
Male subjects with partners who are women of childbearing potential should use a combination 
of the above specified methods for the women along with a male condom during the study and 
for 120 days after the last dose of IP, unless permanently sterile by bilateral orchidectomy.
Subjects should be informed that taking the IP may involve unknown risks to the fetus (unborn 
baby) if pregnancy were to occur during the study. To participate in the study, they must adhere 
to the contraception requirement (described above) for the duration of the study and study period 
up to 120 days after the last dose of IP. Reporting of Pregnancy and Lactation to the Sponsor’s 
Medical Monitor is required (see Section 8.3.8). If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not enter the study.
Collection of Pregnancy Information
Male subjects with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is in this study. This applies 
only to male subjects who receive IP.
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After obtaining the necessary signed consent from the pregnant female partner directly, the 
investigator will record pregnancy information on the appropriate form and submit it to the 
Sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 8 
weeks following the estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure.
Female Subjects who become pregnant

The investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a subject’s 
pregnancy.

The subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the subject and the neonate and the information will 
be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE.

A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring 
at >22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.

Any post-study pregnancy related SAE considered reasonably related to the IP by the 
investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
investigator is not obligated to actively seek this information in former study subjects, he 
or she may learn of an SAE through spontaneous reporting.

Any female subject who becomes pregnant while participating in the study will 
discontinue IP or be withdrawn from the study.
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10.5.
Appendix 5: Medication Guidance
Torsade’s de Pointes
For drugs with risk of Torsade’s de Pointes, refer to

Credible meds: https://www.crediblemeds.org/

New Zealand MedSafe: 
http://www.medsafe.govt.nz/profs/PUArticles/DrugInducedQTProlongation.htm

The Pharmacist: https://www.uspharmacist.com/article/medication-induced-qt-
interval-prolongation-and-torsades-de-pointes
Subjects are prohibited from taking medications listed in Category 1: Drugs with Risk of 
Torsades de Pointes. Caution is warranted when administering AL101 to subjects taking drugs 
associated with prolongation of QTc listed in Category 2: Drugs with Possible Risk of Torsades 
de Pointes.
Although ondansetron is listed in Category 1, because the effect on QTc has been shown to occur 
at the highest drug concentrations, IV doses of ondansetron not greater than 16 mg are permitted, 
as are any oral doses.
Additional information on ondansetron is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020103s035_020605s019_020781s0
19lbl.pdf
CYP3A4 Guidance
AL101 is a substrate for CYP3A4. The list below provides example. Investigator to contact 
Sponsor’s Medical Monitor for clarification and guidance if there is any uncertainty about the 
specific concomitant medication that is either not listed in this Appendix or in the link 
(https://drug-interactions.medicine.iu.edu/MainTable.aspx). The Sponsor’s Medical Monitor will 
have access to drug-drug interaction database software (either Lexi-Interact, Micromedex Drug 
Interactions, iFacts, Medscape, and Epocrates).
Strong Inhibitors: A strong inhibitor is one that causes ≥ 5-fold increase in the plasma AUC 
values of a coadministered substrate. Strong inhibitors of CYP3A4 are prohibited while subjects 
are on treatment with AL101. Some examples of strong inhibitors of CYP3A4 are:
clarithromycin 
nelfinavir
posaconazole
Telithromycin
indinavir 
itraconazole
Nefazodone
ritonavir
ketoconazole
saquinavir
voriconazole
In addition, excessive consumption of the following foods should be avoided:
Grapefruit and grapefruit juice
Seville oranges and Seville orange juice
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Strong Inducers: A strong inducer is one that causes ≥ 80% decrease in the plasma AUC values
of a coadministered substrate. Strong Inducers of CYP3A4 are prohibited while subjects are on
treatment with AL101. Some examples of strong inducers of CYP3A4 are:
avasimine 
phenytoin
St. John’s wort
carbamazepine 
rifampin
These lists are not meant to be all inclusive. Please consult individual drug labels for further
information. Additional information is also available at:
http://www.medicine.iupui.edu/clinpharm/ddis/table.asp
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10.6.
Appendix 6: Summary of Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1
Disease response will be evaluated using the Response Evaluation Criteria in Solid Tumors 
(RECIST) criteria (version 1.1). The following appendix summarizes the process for selecting 
baseline measurable lesions and deriving the appropriate response at subsequent imaging time 
points. For specific details related to the response criteria please refer to the published RECIST 
criteria (version 1.1) (Eisenhauer, 2009).
Establishing a Baseline Overall Tumor Burden:
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. The disease 
burden at baseline will be categorized into target and non-target lesions.
Target Lesions:

Identify a maximum of 5 target lesions (up to 2 target lesions per organ).

Target lesions must be measurable; where measurable is defined:

10 mm in the longest diameter by CT (preferred) or MRI scan (or no less than double 
the slice thickness) for non-nodal lesions and ≥ 15 mm in short axis for nodal lesions

10 mm caliper measurement by clinical exam

20 mm by chest X-ray
NOTE: Regardless of the imaging modality blastic bone lesions will not be 
selected as target lesions. Lytic or mixed lytic-blastic lesions with a measurable 
soft tissue component ≥ 10 mm can be selected as target lesions.
NOTE: Lesions having undergone prior intervention (e.g., previous irradiation) 
will not be selected as target lesions unless there has been a demonstration of 
progress in the lesion.

Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.

Calculate the sum of the diameters (SOD) of all target lesions.

For non-nodal lesions: the longest diameter should be included in the sum of 
diameters

For nodal lesions: the short axis measurement (i.e., widest dimension perpendicular 
to the long axis) should be included in the sum of diameters
Non-Target Lesions:

All remaining lesions (including pathological lymph nodes) are followed as non-target lesions. 
There is no limit to the number of non-target lesions that can be recorded at baseline. 
Baseline measurements are not required for non-target lesions.
Evaluation of Tumor Burden at Subsequent Assessments:
Please refer to the SoA (Table 1) for the timing of subsequent imaging assessments.
Target Lesions:
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Target lesions are measured at every subsequent assessment and an overall SOD is calculated. 
Target lesions are assessed as Complete Response (CR), Partial Response (PR), Stable Disease 
(SD), Progressive Disease (PD), or Not All Evaluated (NAE) at every time point based on the 
calculated SOD.
Target Assessment
Evaluation Definition
Complete Response (CR)
CR is declared if ALL of the following are true for target lesions:

The disappearance of all non-nodal target lesions

Any pathological lymph nodes must have a reduction in short 
axis to <10 mm.
Partial Response (PR)
PR is declared if there is a decrease of at least 30% in the SOD of 
target lesions compared to the baseline SOD of target lesions.
Progressive Disease (PD)
PD is declared if ANY of the following are true for target lesions:

SOD of all target lesions increases at least 20% compared to the 
smallest SOD recorded from any prior assessment
NOTE: In addition to the relative increase at least 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.
OR

The appearance of one or more new lesions.
Stable Disease (SD)
SD is declared if target lesion assessment does not meet criteria for 
PR, PD, or CR.
Non-Target Lesions:
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed qualitatively at subsequent assessments. Non-target lesions are 
assessed as CR, PD, non-CR/non-PD (NCNP), or NAE at every time point.
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Non-Target Assessment
Evaluation Definition
Complete Response (CR)
CR is declared if ALL of the following are true for non-target lesions:

Disappearance of all non-target lesions and normalization of 
tumor marker level.

All lymph nodes must be non-pathological in size (<10 mm 
short axis).
Non-CR/Non-PD (NCNP)
NCNP is declared when persistence of one or more non-target 
lesion(s) and/or the maintenance of tumor marker level above the 
normal limits is observed.
Progressive Disease (PD)
PD is declared if ANY of the following are true for non-target lesions:

Unequivocal Progression of existing non-target lesions.
NOTE: Unequivocal Progression of non-target disease is 
defined as an overall level of substantial worsening in non-
target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. A modest increase in the size 
of one or more non-target lesion(s) is usually not sufficient to 
quality for unequivocal progression. The designation of overall 
progression solely on the basis of change in non-target disease 
in the face of SD or PR of target disease should therefore be 
extremely rare.
OR

The appearance of one or more new lesions.
New Lesions:
The determination of new lesions should be unequivocal and not be attributable to differences in 
the scanning technique, change in modality, or findings thought to represent something other 
than tumor. This is particularly important when the subject’s target lesions show PR or CR.
A lesion identified at a subsequent time point in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. This underscores the 
importance of scanning all anatomical locations that are suspected to contribute to disease 
burden at baseline. 
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Overall Time Point Response Assignment at Subsequent Assessments:
Once the Target-Lesion, Non-Target Lesion, and New Lesion Assessments have been completed 
for a subsequent imaging assessment, an Overall Time Point Response may be assigned.
Target Lesion 
Assessment
Non-Target Lesion 
Assessment
New Lesion 
Assessment
Overall Time Point 
Response
CR
CR
No
CR
CR
NCNP
No
PR
CR
NAE
No
PR
PR
NCNP or NAE
No
PR
SD
NCNP or NAE
No
SD
NAE
NCNP
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR - Complete Response, PR - Partial Response, SD - Stable Disease, PD - Progressive Disease, 
NCNP - Non-CR/Non-PD, NAE - Not All Evaluated, NE - Not Evaluable 
Should you have any questions with regards to the imaging assessment requirements for this 
study protocol, please contact the Medical Monitor.
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10.7.
Appendix 7: Patient Reported Outcomes
Quality of Life – EORTC QLQ-C30
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Quality of Life Breast Cancer Module - EORTC QLQ-BR45
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© 2018 EORTC Quality of Life Group. All right reserved. Phase IV module
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10.8.
Appendix 8: Abbreviations
Abbreviation Term
Description
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase 
aPTT
Activated partial thromboplastin time 
ANC
Absolute neutrophil count 
ASCO
American Society of Clinical Oncology 
AST
Aspartate aminotransferase 
BC
Breast cancer
BMI
Body mass index 
BOR
Best overall response 
BUN
Blood urea nitrogen 
CAP
College of American Pathologists 
CBC
Complete blood count 
CBR
Clinical benefit response rate 
cfDNA
Cell-free DNA
CNS
Central nervous system 
CR
Complete response 
CrCl
Creatinine clearance 
CRO
Contract research organization 
CSC
Cancer stem cell
CTA
Clinical trial assay
CTC
Circulating tumor cell
CTCAE
Common terminology criteria for adverse events 
DILI
Drug-induced liver injury 
DLT
Dose limiting toxicity 
DMC
Data monitoring committee 
DNA
Deoxyribonucleic acid
DOR
Duration of response
ECOG
Eastern cooperative oncology group 
eCRF
Electronic case report form
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Abbreviation Term
Description
EORTC QLQ-BR45
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Breast Cancer 45 questions
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire 30 questions
EOS
End of study 
ER
Estrogen receptor 
FFPE
Formalin-fixed paraffin embedded 
FISH
Fluorescence in situ hybridization 
FSH
Follicle stimulating hormone 
GI
Gastrointestinal 
hCG
Human chorionic gonadotropin 
HER2
Human epidermal growth factor receptor 2
HIPAA
Health Insurance Portability and Accountability Act 
HIV
Human immunodeficiency virus 
HR
Hormone receptor
IB
Investigator’s Brochure 
ICF
Informed consent form 
IEC
Independent Ethics Committees 
IHC
Immunohistochemistry 
IP
Investigational product
IRB
Institutional Review Boards 
ISH
In situ hybridization 
IXRS
Web/Voice Response System 
IUO
Investigational use only
IV
Intravenous
LDT
Laboratory developed test
MedDRA
Medical Dictionary for Regulatory Activities 
MTD
Maximum tolerated dose 
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute 
NICD
Notch intracellular domain 
NGS
Next generation sequencing 
NYHA
New York heart association 
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Abbreviation Term
Description
ORR
Overall response rate 
OS
Overall survival 
OTC
Over the counter
PARP
Poly (ADP-ribose) polymerase
PD
Progressive disease
PD-L1
Programmed death-ligand 1
PDX
Patient-derived xenograft 
PFS
Progression free survival 
PO
Per os 
PP
Per-protocol 
PR
Partial responses 
Q8h
Every 8 hours
QD
Once daily
QoL
Quality of life 
QW
Weekly 
RECIST
Response Evaluation Criteria in Solid Tumors 
SAE
Serious adverse event
SAP
Statistical analysis plan 
SD
Stable disease
SoA
Schedule of Activities 
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
TIC
Tumor-initiating cell
TNBC
Triple negative breast cancer 
TSH
TSH
ULN
Upper limit of normal 
WOCBP
Women of childbearing potential 
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10.9.
Appendix 9: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Prior Amendments
Amendment 1 (V2.0); 06 April 2020
Section
Summary of Change
Rationale for Change
Section1.1 Synopsis
Section 1.2 Study Schema
Section 2.1 Study Rationale
Section 2.3.3 Overall Benefit 
Risk Conclusion
Section 4.1 Study Design
Section 4.2.1 Rationale for 
Study Population
Section 5.1 Inclusion criteria
Modify study population (delete 
Notch activated endocrine 
refractory breast cancer)
Per FDA suggestion, this 
population may be included in 
the future once there is 
sufficient data on the response 
of subjects with TNBC
Section 1.1 Synopsis
Section 1.2 Study Schema
Section 4.1 Study Design
Section 9.1 Statistical 
hypothesis and sample size 
determination
Add a lead-in cohort with 6 
subjects at dose level 6 mg QW
Modify sample size.
Per FDA request, as a safety 
precaution, to allow safety 
evaluation of 6 mg QW in 6 
subjects before proceeding to 
enroll the rest of the subjects
Section 1.1 Synopsis
Section 1.2 Study Schema
Section 4.1 Study Design
Section 6.1 Investigational 
Product Administered
Section 9.1 Statistical 
hypothesis and sample size 
determination
Clarify that Stage 1 will be 
initiated at either 4 mg or 6 mg 
QW
There will be evaluation of 6 mg 
QW in 6 subjects before 
proceeding to enroll the rest of 
the subjects; a decision will be 
made to continue at 6 mg QW or 
change to 4 mg QW 
Section 1.3 Schedule of 
Activities
Section 8.4 Biomarkers and 
Pharmacokinetics
Add PK assessment
Clarify stipulations for tumor 
biopsy collection
Per FDA request
Section 4.3 Justification for 
Dose
Update dose justification section
Per FDA request
Section 5.1 Inclusion criteria
Clarified that prior PARP 
inhibitor therapy is acceptable
To adjust to changing therapy 
landscape
Section 5.2 Exclusion criteria
Clarify excluded bilirubin value 
for Gilbert’s syndrome
For clarity
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Section
Summary of Change
Rationale for Change
Section 6.4 AL101 Dose 
Modification and Toxicity 
Management
Section 8.3.5.4 Hepatic Function 
abnormalities
Clarify dose modification 
guidelines.
Clarify, where relevant, that 
subjects will be discontinued 
from IP, not the study.
Safety precaution
Section 1.3 Schedule of 
Activities
Appendix 2 clinical labs
Replace triglyceride with 
complete lipid panel
Safety precaution
Section 6.6.2
Add “approximately” to 
describe the steroid pre- and 
post-dose medication schedule
To provide the sites flexibility in 
case they cannot meet the exact 
dosing schedule
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11.
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