Clinical trial NCT03691207
Conditions: Adenoid Cystic Carcinoma
Sponsor: Ayala Pharmaceuticals, Inc,
Start date: 2018-12-14; Completion date: 2022-12-02
Enrollment: 87 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, non comparative, open label, multicenter study of AL101 in patients with recurrent or metastatic ACC who harbor NOTCH 1,2,3,4 activating mutations.

Detailed description:
This is a Phase 2, non-comparative, open-label, multicenter study of AL101 in patients with recurrent or metastatic ACC who harbor NOTCH 1,2,3,4 activating mutations.

The study includes 2 cohorts, ran in a sequential fashion:

Cohort 1 - AL101 4 mg once weekly (QW) intravenously (IV) Cohort 2 - AL101 6 mg QW IV

Arms: arm 1: AL101 is an inhibitor of gamma secretase-mediated Notch signaling.
Interventions: intervention 1: AL101
Intervention descriptions: intervention 1: AL101 is a small-molecule that inhibits gamma secretase, an enzyme which plays a key role in the activation of the Notch signaling pathway by releasing the Notch intracellular domain (NICD) of all four Notch receptors from the membrane.

In patients with aberrant Notch signaling, AL101 may inhibit Notch signaling and potentially impede tumor growth.The drug is administered intravenously

Protocol documents:
Prot_000.pdf: 
Confidential
CLINICAL STUDY PROTOCOL
ACCURACY STUDY
A PHASE 2, OPEN-LABEL, MULTI-CENTER STUDY OF AL101 IN 
PATIENTS WITH ADENOID CYSTIC CARCINOMA (ACC) BEARING 
ACTIVATING NOTCH MUTATIONS
Sponsor:
Ayala Pharmaceuticals, Inc,
1313 N. Market Street, Suite 5100, Wilmington, DE 19801, USA
Principal 
Investigator:
Renata Ferrarotto, MD, Associate Professor
Department of Thoracic Head and Neck Medical Oncology,
Division of Cancer Medicine, University of Texas, MD Anderson Cancer 
Center
Houston, TX
IND Number:
110,405
EudraCT Number:
2019-000309-64
Protocol Number:
AL-ACC-01
Study Phase:
2
Investigational 
Product:
AL101 (formerly known as BMS-906024)
Contract Research 
Organization:
Precision for Medicine 
Sponsor Contact:
Gary Gordon, MD, garyg@ayalapharma.com mailto:
Medical Monitor: 
Gilad Gordon, MD, Ayala Pharmaceuticals, Inc.
Final Protocol Date 
& Version:
Version 4.0, Amendment 3.0, 27 August 2020 
(Supersedes Protocol V3.0, Amendment 2)
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.
Clinical Study Protocol AL-ACC-01
Document Number: CL6-0000866
Document Version: 1.0
Effective Date: 23-Sep-2020
Document State: Effective (Controlled) 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Protocol Title
ACCURACY: A Phase 2, open-label, multi-center study of AL101 
in patients with adenoid cystic carcinoma (ACC) bearing activating 
notch mutations
Protocol Number
AL-ACC-01
Version and Date
Version 4.0,  27 August 2020
(Supersedes Protocol V3.0, Amendment 2)
Amendment No. 
3.0
IND Number
110,405
EudraCT Number:
2019-000309-64
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, Country
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PROTOCOL DOCUMENT HISTORY
Document
Date
Protocol V4.0, Amendment 3, Global
27 August 2020
Protocol V3.0, Amendment 2, Global
20 December 2019
Protocol V2.3, Amendment 1.3 France-specific
15 August 2019
Protocol V2.2, Amendment 1.2 UK-specific
01 August 2019
Protocol V2.1, Amendment 1.1 UK-specific
25 July 2019
Protocol V2.0, Amendment 1, Global
22 March 2019
Protocol V1.2, Canada-specific
25 September 2018
Protocol V1.1, Canada-specific
20 September 2018
Original Protocol V1
19 July 2018
CURRENT PROTOCOL AMENDMENT SUMMARY OF CHANGES
AMENDMENT 3 (V4.0); 27 AUGUST 2020
Protocol Section
Summary of Change
Rationale for Change
Protocol synopsis
Schedule of Activities (Table 1)
3 Study design
5.4 Biomarkers
Clarify that on-treatment 
biopsy will be collected 
(instead of at progression)
Clarify that blood samples 
for biomarkers will be 
collected on the same day as 
on-treatment tumor biopsy
To ensure biopsies are 
collected on treatment and 
increase compliance to the 
protocol 
To allow correlative analysis
Protocol synopsis
9.2 Sample size consideration
Clarify text regarding 2nd look
For clarity purposes
Schedule of Activities (Table 1)
5 Study procedure
5.1.1 RECIST, Table 2
Delete reference to ‘Early 
Discontinuation’
In this study end of study and 
early discontinuation are 
synonymous 
4.2 Exclusion criteria
Delete exclusion criterion 9
Update exclusion criterion 
11f (creatinine)
Based on data reanalysis, 
excluding nucleoside 
analogues is not supported 
with clinical or nonclinical 
data
Allow inclusion based on 
normal creatinine values, as 
well as sufficient GFR, as 
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Protocol Section
Summary of Change
Rationale for Change
AL101 is not expected to 
impact renal function
4.5 Early withdrawal of patients 
from therapy or assessment
Clarify, where relevant, that 
subjects will be discontinued 
from IP, not the study.
Clarify that subjects being 
managed with dose 
interruption for toxicity 
should have their study 
assessments followed per 
SoA.
Add reference to dose 
modifications and toxicity 
management.
For continued care and safety of 
subject during the dose 
interruption
5.2.8 Safety laboratory 
assessments
6.6 Dose modification and 
toxicity management guidelines 
(Table 5)
Add lipase for subjects 
experiencing ≥Grade 2 diarrhea 
adverse events
Per request of the Spanish 
competent authority
6.6 Dose modification and 
toxicity management guidelines 
(Table 5)
8.4.2 Colitis (Table 9)
Clarify dose modification 
guidelines for diarrhea, 
colitis, gastric hemorrhage, 
and non-hematologic lab 
abnormalities and allow for 
re-escalation with Sponsor’s 
Medical Monitor approval.
Introduce change in regimen 
(2 weeks on / 1 week off) for 
first episode of Grade 2 or 3 
diarrhea and Grade 2 Colitis 
before dose reduction on 
subsequent episodes
Safety precaution 
To allow investigators to use 
a 2 weeks on / 1 week off 
regimen at 6 mg QW, before 
implementing dose 
reduction. The aim is to 
introduce a scheduled dose 
interruption to prevent 
recurrence of toxicity
6.6 Dose modification and 
toxicity management guidelines 
(Table 5)
6.6.1 Treatment of infusion 
reactions
8.2 Serious Adverse Event 
(SAE)
8.4 Adverse events of Special 
Interest (AESI)
8.4.3 Infusion reactions 
including anaphylaxis
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
Safety precaution
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Protocol Section
Summary of Change
Rationale for Change
7.1.1 Premedication to prevent 
hypersensitivity reaction
7.1.2 Premedication with 
corticosteroids
Reorganized and added 
sections relating to 
premedication
Refer to Section 7.1.2 
throughout the protocol, as 
relevant
For safety precaution 
For consistency
General
Minor clarification 
throughout protocol 
including number of 
sites/locations, deletion of 
enrollment duration, study 
manual name(s), timing of 
confirmation scans and 
quality of life
Correct typos, hyperlinks, 
style and formatting
Align across protocol 
sections
On title page, update vendor 
(CRO) name, investigator 
title, Sponsor contract 
information
For consistency and clarify
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PROTOCOL SYNOPSIS
Study Title
A Phase 2, Open-Label, multi-center Study of AL101 in patients with adenoid cystic carcinoma 
(ACC) bearing activating Notch mutations
Protocol No. AL-ACC-01
Study Phase
Phase 2
Clinical Sites
Approximately 16 sites in North America, and 10 sites in Europe 
and Israel
Study Rationale
AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling that is 
currently under development as an antitumor/antiangiogenic agent for single use or in 
combination with cytotoxic agents as well as other targeted agents in the treatment of tumor 
growth and metastasis. A large body of experimental evidence supports a causal role of 
activating Notch mutations in tumorigenesis. In adenoid cystic carcinoma (ACC), sequencing 
of tumor samples revealed genomic alterations in the Notch pathway in a subset of patients with 
a distinct ACC phenotype. ACC patients with NOTCH1 mutations have an aggressive disease 
with a distinct pattern of metastasis and worse prognosis than their wild type counterparts. In 
addition to NOTCH1 mutations, other NOTCH mutations (2, 3, 4) were identified in ACC. There 
are currently no available therapies for these patients. Therefore, ACC with Notch pathway 
activation represents a high unmet therapeutic need.
Objectives
Endpoints
Primary

To assess the clinical activity of AL101 
using radiographic assessments and 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 in ACC 
patients 
with 
activating 
Notch 
mutations

Objective response rate (ORR; complete 
response [CR] and partial response [PR]) 
by RECIST v1.1 as determined by 
Investigator review. For patients with bone-
exclusive disease, the modified MD 
Anderson (MDA) bone criteria will be used 
to access response (see Table 11).
Note: Investigator review will be done in 
accordance to FDA “Clinical Trial Imaging 
Endpoint Process Standards Guidance for 
Industry” (April 2018).1
1 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm268555.pdf
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Secondary

Clinical activity assessments

Duration 
of 
response 
(DOR) 
by 
Investigator review based on RECIST v1.1.

Progression 
free 
survival 
(PFS) 
by 
Investigator review based on RECIST v1.1.

Overall survival (OS).

To assess quality of life (QoL) in ACC 
patients 
with 
activating 
Notch 
mutations.

Change 
from 
baseline 
in 
European 
Organization for Research and Treatment 
of Cancer Quality of Life Questionnaire 30 
Questions (EORTC QLQ-C30).

To confirm safety and tolerability of 
AL101 in ACC patients with activating 
Notch mutations.

Frequency, duration and severity of adverse 
events (AEs) and serious adverse events 
(SAEs).

Incidence 
of 
clinically 
significant 
laboratory abnormalities; safety laboratory 
evaluations includes complete blood count 
(CBC), blood biochemistry and urinalysis.

To obtain a set of population parameters 
and to identify covariates that affect 
systemic exposure to AL101 and 
metabolite(s).

A population (mixed-effects) PK approach 
will be used to analyze the concentration 
data.
For AL101 and metabolite(s), one- and two-
compartment linear models will be applied to 
the data
Exploratory

To 
establish 
correlation 
between 
positive Notch1 intracellular domain 
(NICD1) stain and Notch1 activating 
mutations.

To establish the correlation between 
mutations in Notch and associated 
genes and response or resistance to 
investigational product.

Predictive biomarkers of response or 
resistance to the investigational product 
will be explored:

Immunohistochemistry (IHC): Tumor 
specimens will be stained for NICD1 
and other biomarkers such as, but not 
limited to: programmed death ligand 
(PD-L1), Ki-67 and FBXW7.

Next Generation Sequencing (NGS): 
Mutational analysis will be performed in 
tissues samples as well as in cell-free 
DNA (cfDNA).

Pharmacodynamic markers indicative of 
drug activity will be measured, including 
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HES-1 and others such as, but not limited 
to: HES-4, HES-5, HEY-1, 2, HEYL, HIF1 
alpha, and others.
Study Design
This is a Phase 2, non-comparative, open-label, multicenter study of AL101 in patients with 
recurrent or metastatic ACC who harbor NOTCH 1,2,3,4 activating mutations.
The study includes 2 cohorts, ran in a sequential fashion:

Cohort 1 – AL101 4 mg once weekly (QW) intravenously (IV)

Cohort 2 – AL101 6 mg QW IV
Cohort 1 will continue to enroll to reach up to a maximum of 45 patients. Cohort 2 will open 
for enrollment up to a maximum of 42 patients.
Prior to entering the study, to determine eligibility, potential candidates will undergo 
pre-screening assessment and confirmation for the presence of activating Notch mutations. 
Available mutation status from prior tests with any commercially available or locally 
developed NGS assay are acceptable. In Europe any commercially available CE marked 
device shall be used (for country specific requirements refer to Appendix E).
If historical genotyping results are not available, testing will need to be conducted during pre-
screening using a laboratory developed or commercially available NGS assay to identify and 
confirm an activating Notch mutation. Any newly characterized mutation (such as tandem 
duplication, variant allele frequency, variants of unknown significance, etc.), will be evaluated 
with the Sponsor on a case-by-case basis. Pre-screening study-specific assessments may be 
done while potential candidates are on other therapy provided that a separate pre-screening 
informed consent form is signed.
Patients with activating Notch mutations will then undergo screening assessments to 
determine study eligibility over a 28-day Screening period. Enrollment of patients with bone 
exclusive disease should be discussed and approved by the Sponsor’s Medical Monitor before 
enrollment (refer to inclusion criterion 5 in Section 4.1). For all patients, prior treatments and 
responses to such treatments, including radiological images and reports, within a year of study 
entry, will be collected as part of the medical history; for patients who are currently enrolled, 
this information will be collected retrospectively.
Starting on Cycle 1, Day 1, eligible patients will enroll into the study and receive AL101, 
either  4 mg intravenously (IV) weekly (QW) in Cohort 1 or 6 mg QW IV in Cohort 2, on 
Days 1, 8, 15, and 22 of each 28-day cycle until disease progression, unacceptable toxicity, or 
consent withdrawal. For patients with radiological progression, investigational treatment may 
be continued as long as the patient is having clinical benefit, is agreed to by the patient and 
physician and approved by the Sponsor’s Medical Monitor. 
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Paired tumor biopsies will be collected at screening (fresh or archival2 within 3 years) and on-
treatment at Cycle 4 Day 1 ±28 days (provided medically safe and not contraindicated). 
Samples will be sent to a central vendor for NGS analysis. Formalin-fixed paraffin embedded 
(FFPE) slides will be evaluated by IHC for NICD1 stain. On the day of the on-treatment 
biopsy, blood will also be drawn for PK and biomarker assessments.
During the Treatment period, patients will undergo radiographic assessments every 8 weeks 
(±3 days) for review by the Investigator. Scans will be collected and held for possible future 
retrospective evaluation by an Independent Central Review (ICR). Other assessments will be 
done as specified in the Schedule of Activities (SoA; Table 1), including safety exploratory 
biomarkers. 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.
All patients will undergo end of study (EOS) visit 30 days post last treatment and will be 
contacted by phone every 3 months thereafter to determine survival status. In patients who 
discontinued investigational product due to toxicity, radiographic imaging will be done every 
3 months until disease progression or until the patient initiates another anti-cancer therapy.
Data Monitoring Committee (DMC) review: Throughout the study, the independent DMC 
will monitor safety and efficacy parameters at approximately quarterly intervals, after at least 
3 patients have been treated for at least 2 cycles (after the first on-treatment radiographic 
assessment). Further details are specified in the DMC charter.
Study Duration
Study participation for each patient consists of:
Screening period: 
up to 28 days
Treatment period: 
Weekly treatment until disease progression3, unacceptable toxicity, 
or consent withdrawal
EOS: 
30 days after the last administration of investigational product
Long-term follow-up: 
Every 3 months
Diagnosis and Main Criteria for Inclusion
Adult patients with histologically confirmed adenoid cystic carcinoma (ACC) who have:
2 If an archival tumor block or 25 unstained slides are not available, the patient will be required to have a fresh 
tumor sample obtained at screening.
3 For patients with radiological progression, investigational product may be continued as long as the patient is 
having clinical benefit, is agreed to by the patient and physician and approved by the Sponsor’s Medical Monitor.
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
Histologically confirmed ACC with known NOTCH 1/2/3/4 activating mutation that is 
recurrent or metastatic, not amenable to potentially curative surgery or radiotherapy.

Evidence of radiographic or clinical disease progression within 6-months of signing 
informed consent; newly diagnosed metastatic patients will be allowed.

At least 1 target lesion that is measurable per RECIST v1.1 for patients with nodal or 
visceral metastasis. Patients with bone exclusive disease will also be eligible after 
consultation and approval with Sponsor’s Medical Monitor before enrollment and only if 
bone lesions are evaluable and measurable by CT or MRI as per modified MD Anderson 
(MDA) Criteria (see Table 11 in Appendix C).
For full list of inclusion and exclusion criteria, please refer to Sections 4.1 and 4.2, respectively.
Investigational Product Route and Dosage Form
AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling. 
AL101 will be administered IV at the dose of 4 mg every 7 days (±2 day; QW) in Cohort 1 
and at the dose of 6 mg every 7 days (±2 day; QW) in Cohort 2 over 28-day cycles until 
disease progression, unacceptable toxicity, or consent withdrawal. For patients with 
radiological progression, investigational product can be continued as long as the patient is 
having clinical benefit, is agreed to by the patient and physician and approved by the 
Sponsor’s Medical Monitor. 
AL101 injection has been developed as a single-use sterile solution (1.2 mg/mL) for IV 
administration in clinical studies; each vial contains 5 mL (equivalent of 6 mg per vial). It is 
formulated as a sterile concentrate containing Cremophor® and ethanol and will be diluted 
with 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP 
(D5W) to concentrations between 0.01 mg/mL and 0.06 mg/mL. In order to reduce the risk of 
infusion reactions caused by Cremophor, use premedication per institution guidelines such as 
H1- and H2-blockers (diphenhydramine and ranitidine or equivalents) or dexamethasone (refer 
to Section 7.1.2) will be given. For any questions, please contact the Sponsor’s Medical 
Monitor.
Statistical Methods
Null Hypothesis
A response rate of 8% or less is considered not clinically significant.
Sample Size
The study was initiated as a Simon’s two-stage optimal design. The study passed the futility 
analysis in Stage 1 of the Simon two-stage design and is currently continuing to enroll 
patients. While the data on Cohort 1 (4 mg QW) is maturing, the study will enroll up to a 
maximum of 45 patients in Cohort 1 and, in parallel, will be expanded with the addition of 
Cohort 2 (6 mg QW). The study will continue enrolling a total of 42 patients in Cohort 2, 
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 patient. A second look is going 
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to be considered at 50% of the total information fraction (21 patients) for Cohort 2, with the 
study stopped for futility if two or fewer subjects respond .The expansion of Cohort 1 to a 
maximum of 45 patients and Cohort 2 to a maximum of 42 patients will provide at least 80% 
power in each cohort to test the hypothesis of achieving an increase of the response rate from 
8% to 25% using a type I error of 5%.
Analysis Population

Safety analysis set consists of all enrolled patients who received at least one dose of 
investigational product (even a partial dose).

Efficacy evaluable set includes all patients who receive investigational product and have 
at least one post baseline on-study assessment of tumor response.

Per-protocol (PP) analysis set consists of all efficacy evaluable patients without major 
protocol deviations, as defined by the Sponsor prior to database lock

PK analysis set includes all patients who receive investigational product and have at least 
one post baseline evaluable PK sample.
General Statistical Methods
Statistical analyses will be performed using SAS® v9.4 or higher (SAS Institute, Cary NC, 
USA).
Evaluation of data will consist primarily of descriptive summary statistics and data listings. 
Summary statistics for continuous variables will include the sample size (n), mean, standard 
deviation, median, minimum and maximum. Categorical variables will be summarized in 
frequency tables. Time to event variables will be analyzed using Kaplan-Meier methods.
If any statistical tests are performed, they will be one-sided, at the 5% significance level. 
Where confidence limits are appropriate, the confidence level will be 95%, unless otherwise 
stated.
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.
Efficacy Analysis
Estimates of ORR and other response proportions will be presented together with 95% 
confidence intervals calculated using the Clopper-Pearson method. Kaplan-Meier estimation 
will be used for the analysis of time-to-event endpoints, including DOR, PFS, and OS. 
Primary efficacy analyses will be performed on the efficacy evaluable set. Refer to the SAP 
for more details.
Safety and Tolerability Analysis
Safety will be assessed on the basis of AEs, clinically significant laboratory abnormalities, 
concomitant medication use, vital signs, pain assessments, and physical examination data for 
patients in the safety analysis set.
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Hematology and clinical chemistry data will be summarized by change from baseline and 
worst-case toxicity grade shift relative to baseline. Deaths will be listed by primary cause and 
date relative to last dose of investigational product.
Interim Analysis
No formal interim analysis is planned.
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SCHEDULE OF ACTIVITIES
Table 1
Schedule of Activities (SoA)
Visit window will be ±2 days during treatment period, except for imaging ±3 days; EOS and Long-term follow-up will be ±7 days.
Treatment Perioda  (by cycles and days of cycle)
Pre-
Screena
Screening 
Period 
(days)
Cycle 1
Cycle 2
Cycles 3+
End of 
Study(EOS) 
Visit 
Long-
Term 
Follow-up
1 cycle = 28 days (4 
weeks)
Assessments 
-28 to -1
D1 D8 D15 D22 D1 D8 D15 D22
D1
D8 D15
D22
30 days post last 
IP
Every 3 
months
Prescreen informed consent
X
Informed consent
X
NGS Assay
Xb
Tumor biopsyc
X
Cycle 4 (±28 
days) only
Pre-identification form 
(Confirmation of Notch 
activating mutation)
Xb
Medical & ACC disease 
history (including therapy)
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical examd
X
X
X
Symptoms directed PE
X
X
X
X
X
X
X
X
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
Peripheral blood 
lymphocyte subsets
X
X
X (every 8 weeks)
Serum chemistryf
X
Xg
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
Xh
X
Triglycerides
X
X
X
X
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Treatment Perioda  (by cycles and days of cycle)
Pre-
Screena
Screening 
Period 
(days)
Cycle 1
Cycle 2
Cycles 3+
End of 
Study(EOS) 
Visit 
Long-
Term 
Follow-up
1 cycle = 28 days (4 
weeks)
Assessments 
-28 to -1
D1 D8 D15 D22 D1 D8 D15 D22
D1
D8 D15
D22
30 days post last 
IP
Every 3 
months
Thyroid function (TSH, 
total T3, free T4)
X
X (every 12 
weeks)
HbA1c
X
X (every 8 weeks)
HIV, Hepatitis B and C 
X
Coagulation factors
X
X
Xi
PSA (male only)
X
Urinalysisj
X
X
12 lead ECGk
X
X (every 12 
weeks)
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testl
X
X
X
X
X
AL101 infusion
X
X
X
X
X
X
X
X
X
X
X
X
Imaging and Radiologic 
evaluationm
X
X (every 8 weeks 
X 
Xm
MRI or CT brain with 
contrast
X
EORTC-QLQ-C30 n
X
X
C4D1 and every 4 
weeks thereafter
X
Blood for biomarkers: 
mRNA / 
pharmacodynamicso
X
X
X
X
Cycle 4±28 days 
(on day of on-
treatment biopsy)
X 
(every 
8 
weeks)
X
Blood for biomarkers: 
cfDNA p
X
X
Cycle 4±28 days 
(on day of on-
treatment biopsy)
X 
(every 
8 
weeks)
X
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Treatment Perioda  (by cycles and days of cycle)
Pre-
Screena
Screening 
Period 
(days)
Cycle 1
Cycle 2
Cycles 3+
End of 
Study(EOS) 
Visit 
Long-
Term 
Follow-up
1 cycle = 28 days (4 
weeks)
Assessments 
-28 to -1
D1 D8 D15 D22 D1 D8 D15 D22
D1
D8 D15
D22
30 days post last 
IP
Every 3 
months
Blood for population PKq
X
X
X
X
X
Cycle 4±28 days 
(on day of on-
treatment biopsy)
Overall survival
 / visit
Abbreviations: CBC = Complete blood count; EOS = end of study, ECOG = Eastern Cooperative Oncology Group; EORTC-QLQ-C30 = European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire 30 questions; HbA1c = glycosylated hemoglobin; HIV = human immunodeficiency virus; IHC = immunohistochemistry; IP = 
investigational product; NICD1 = Notch1 intracellular domain; NGS = Next generation sequencing; PE = physical examination; PK = pharmacokinetics; PSA = Prostate-specific 
antigen; RECIST = Response Evaluation Criteria in Solid Tumors; TSH = thyroid stimulating hormone.
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; 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 confirm the presence of activating Notch mutations. Available 
genotyping results from a laboratory developed or commercially available NGS assay are acceptable. If historical genotyping results are not available, 
patient must sign prescreening ICF, and testing will need to be conducted during pre-screening using a laboratory developed or commercially available 
NGS assay. Available NGS test results will be shared in the Pre-identification form and response confirming activating Notch mutation is required before 
entering screening. Any newly characterized mutation (such as tandem duplication, variant allele frequency, variants of unknown significance, etc.), will 
be evaluated with the Sponsor on a case-by-case basis.
c.
Paired 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 3 years), and at Cycle 4 Day 1 ±28 days or earlier if the patient progressed(fresh sample, provided medically safe and not 
contraindicated). If an archival tumor block or 25 unstained slides are not available, the patient will be required to have a fresh tumor sample obtained at 
screening. Attempts should be made to biopsy lesions which are not considered to be “target lesions” per RECIST 1.1. criteria.
d.
Full physical examination at baseline; targeted physical examination at other time points.
e.
Complete blood count (CBC) includes hemoglobin, hematocrit, platelet count, WBC count, and absolute differential count.
f.
Chemistry includes glucose, blood urea nitrogen (BUN), creatinine, total bilirubin (a direct bilirubin should be obtained if the total bilirubin level is >1.5 
times ULN), albumin, AST (SGOT), ALT (SGPT), alkaline phosphatase (ALP), lactate dehydrogenase, electrolytes (sodium, potassium, chloride, calcium, 
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magnesium, and phosphorus. Creatinine clearance (CrCl) will be conducted at screening only; Calculation of CrCl will be based on acceptable  institution 
standard).
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 2 weeks, with the exception of liver function tests (AST/ALT/ALP/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 (specific gravity, pH, glucose, protein, ketones, and blood) performed at Screening and as clinically indicated.
k.
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 centrally. Clinically significant ECG abnormalities will be recorded on the eCRF. Triplicate ECGs, at least 3 minutes apart, 
will be performed if QTcF is > 500 msec or if the Investigator identifies an ECG finding (for example QT interval prolonged or cardiac arrythmia) that is 
an adverse event and related to investigational product.
l.
Pre-menopausal female patients of childbearing potential only. Urine or serum pregnancy tests are acceptable.
m. CT or MRI with contrast, of the neck, chest, abdomen, and pelvis are acceptable (PET/CT is not allowed for study assessments, unless CT is done with 
IV contrast). Images will be repeated every 8 weeks (±3 days) during treatment period until disease progression. During the Long-term Follow-up visit, 
only in patients who discontinued investigational product due to toxicity, radiographic imaging will be done every 3 months until disease progression or 
until patient initiates another anti-cancer therapy. The same radiographic technique of each region must be used consistently throughout the study. Refer 
to Imaging Manual. 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.
n.
Quality of life questionnaire will be administered every 4 weeks before investigational product administration or receipt of radiological imaging results
o.
For blood mRNA pharmacodynamic biomarker assessments, blood will be drawn on C1D1 and C1D22 at pre-dose (within 1 hour before start of dose), 7 
hours (±1 hour, and 24-48 hours after start of infusion (±1 hour), C1D8 pre-dose (within 1 hour before start of dose), C2D1 pre-dose (within 1 hour before 
start of dose), every odd cycle Day 22 pre-dose (within 1 hour before start of dose), and at confirmed progression.  In addition, a blood sample will be 
collected on the day of the on-treatment biopsy (Cycle 4, Day 1 ±28 days).
p.
For blood cfDNA biomarker assessments, blood will be drawn on C1D1 and C2D1 at pre-dose (within 1 hour before start of dose), and every odd cycle 
Day 22 pre-dose (within 1 hour before start of dose), and at confirmed progression. In addition, a blood sample will be collected on the day of the on-
treatment biopsy (Cycle 4, Day 1 ±28 days).
q.
During Cycle 1, population PK blood samples will be collected as follows:
Dose No. in a given cycle
Cycle / Day
Nominal Day
Hours Relative to Dose (Window)
1
Cycle 1 / Day1
1
Pre-dose (within 1 hour before start of dose)
End-infusion (within 10 minutes of infusion end)
2 hours after start of infusion (± 30 minutes)
4 hours after start of infusion (± 1 hour)
7 hours after start of infusion (±1 hour)
1
Cycle 1 / Day 2 or 3
2 or 3
24 - 48 hours after start of infusion (±1 hour)
2
Cycle 1 / Day 8
8
Pre-dose (within 1 hour before start of dose)
3
Cycle 1 / Day 15
15
Pre-dose  (within 1 hour before start of dose)
4
Cycle 1 / Day 22
22
Pre-dose (within 1 hour before start of dose)
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Dose No. in a given cycle
Cycle / Day
Nominal Day
Hours Relative to Dose (Window)
End-infusion (within 10 minutes of infusion end)
2 hours after start of infusion (±30 minutes)
4 hours after start of infusion (± 1 hour)
7 hours after start of infusion (± 1 hour)
4
Cycle 1 / Day 23 or Day 24
23 or 24
24 - 48 hours after start of infusion (±1 hour)
4
Cycle 2 / Day 1
29
End of Cycle 1 (pre-dose Cycle 2) (within 1 hour 
before start of dose)
In addition, a PK sample will be collected on the day of the on-treatment biopsy (Cycle 4, Day 1 ±28 days).
For PK sample collection instructions/procedures, refer to the Study PK Manual.
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TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL ........................................................................................................................1
APPROVALS ..........................................................................................................................................................2
PRINCIPAL INVESTIGATOR SIGNATURE PAGE........................................................................................2
PROTOCOL DOCUMENT HISTORY................................................................................................................4
CURRENT PROTOCOL AMENDMENT SUMMARY OF CHANGES .........................................................4
AMENDMENT 3 (V4.0); 27 AUGUST 2020 (REVISION 6.0)...........................................................................4
PROTOCOL SYNOPSIS .......................................................................................................................................7
SCHEDULE OF ACTIVITIES............................................................................................................................13
TABLE OF CONTENTS......................................................................................................................................17
GLOSSARY...........................................................................................................................................................21
1
INTRODUCTION...................................................................................................................................24
1.1
THERAPEUTIC INDICATION ..........................................................................................................24
1.2
CURRENT THERAPY.....................................................................................................................24
1.3
INVESTIGATIONAL THERAPY .......................................................................................................24
1.3.1
Nonclinical Studies.......................................................................................................25
1.3.2
Clinical Studies.............................................................................................................25
1.4
STUDY RATIONALE......................................................................................................................27
1.4.1
Dose Selection ..............................................................................................................29
2
STUDY OBJECTIVES AND ENDPOINTS.........................................................................................30
3
STUDY DESIGN.....................................................................................................................................31
4
STUDY POPULATION..........................................................................................................................34
4.1
INCLUSION CRITERIA...................................................................................................................34
4.2
EXCLUSION CRITERIA..................................................................................................................35
4.3
PATIENT IDENTIFICATION ............................................................................................................36
4.4
SCREENING FAILURES..................................................................................................................36
4.5
EARLY WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT .......................................37
4.6
HANDLING OF WITHDRAWALS ....................................................................................................37
4.7
SPONSOR'S TERMINATION OF STUDY...........................................................................................38
5
STUDY PROCEDURES.........................................................................................................................38
5.1
EFFICACY ASSESSMENTS.............................................................................................................39
5.1.1
RECIST v1.1.................................................................................................................39
5.1.2
Patient Reported Outcome: European Organization for Research and Treatment 
of Cancer Quality of Life Questionnaire 30 questions (EORTC QLQ-C30) ...............42
5.2
SAFETY ASSESSMENTS ................................................................................................................42
5.2.1
Adverse Events .............................................................................................................42
5.2.2
Adverse Events of Special Interest...............................................................................42
5.2.3
Medical History and Concomitant Medications...........................................................42
5.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Status...........................43
5.2.5
Vital signs .....................................................................................................................43
5.2.6
ECG ..............................................................................................................................43
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5.2.7
Physical examination....................................................................................................44
5.2.8
Safety Laboratory Assessments....................................................................................44
5.2.9
Pregnancy Test..............................................................................................................45
5.3
POPULATION PHARMACOKINETICS..............................................................................................45
5.4
BIOMARKERS...............................................................................................................................45
5.4.1
Stipulations for Tumor Biopsy .....................................................................................46
6
INVESTIGATIONAL PRODUCT........................................................................................................47
6.1
INVESTIGATIONAL PRODUCT ADMINISTRATION..........................................................................47
6.2
METHOD OF ASSIGNING PATIENTS ..............................................................................................48
6.3
DISTRIBUTION AND SHIPMENT OF THE INVESTIGATIONAL PRODUCT ..........................................48
6.4
STORAGE AND HANDLING OF THE INVESTIGATIONAL PRODUCT AT THE CLINICAL SITE.............49
6.5
ACCOUNTABILITY AND COMPLIANCE OF INVESTIGATIONAL PRODUCT.......................................49
6.6
DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES..............................................49
6.6.1
Treatment of Infusion Reactions...................................................................................59
6.6.2
Guidelines for Management of Diarrhea ......................................................................60
7
STUDY RESTRICTIONS......................................................................................................................61
7.1
PRIOR AND CONCOMITANT THERAPY..........................................................................................61
7.1.1
Premedication to Prevent Hypersensitivity Reaction ...................................................61
7.1.2
Premedication with Corticosteroids..............................................................................62
7.1.3
Allowed Medications....................................................................................................62
7.1.4
Prohibited Concomitant Medication.............................................................................63
7.2
DIETARY AND OTHER RESTRICTIONS ..........................................................................................64
7.3
CONTRACEPTION .........................................................................................................................64
7.3.1
US and Canada..............................................................................................................64
7.3.2
Europe...........................................................................................................................65
7.3.3
Use in Pregnancy ..........................................................................................................66
7.3.4
Use in Nursing Women.................................................................................................66
8
SAFETY AND PHARMACOVIGILANCE .........................................................................................66
8.1
ADVERSE EVENT .........................................................................................................................67
8.1.1
Abnormal Laboratory which Are Considered AEs.......................................................68
8.1.2
Events not considered AEs ...........................................................................................68
8.1.3
AE Assessments............................................................................................................68
8.2
SERIOUS ADVERSE EVENT (SAE)................................................................................................71
8.3
UNEXPECTED ADVERSE EVENT ...................................................................................................71
8.4
ADVERSE EVENTS OF SPECIAL INTEREST ....................................................................................72
8.4.1
Hepatic Function Abnormalities (hepatotoxicity) ........................................................72
8.4.2
Colitis............................................................................................................................72
8.4.3
Infusion Reactions including Anaphylaxis...................................................................74
8.4.4
Keratoacanthoma ..........................................................................................................74
8.4.5
Potential Drug-Induced Liver Injury (DILI) / Hy’s Law..............................................74
8.5
NOTIFICATION OF SERIOUS UNEXPECTED SUSPECTED ADVERSE EVENT ....................................76
8.6
PREGNANCY.................................................................................................................................78
8.7
OVERDOSE...................................................................................................................................78
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9
STATISTICAL ANALYSIS PLAN.......................................................................................................78
9.1
GENERAL.....................................................................................................................................78
9.2
SAMPLE SIZE CONSIDERATION ....................................................................................................79
9.3
ANALYSIS SETS ...........................................................................................................................79
9.4
PATIENT DISPOSITION ..................................................................................................................80
9.5
DEMOGRAPHIC AND BASELINE CHARACTERISTICS.......................................................................80
9.6
EFFICACY.....................................................................................................................................80
9.6.1
Definition of Efficacy Endpoints..................................................................................80
9.6.2
Efficacy Analysis..........................................................................................................80
9.7
SAFETY AND TOLERABILITY ANALYSIS.......................................................................................81
9.8
INTERIM ANALYSIS......................................................................................................................81
10
DATA MANAGEMENT ........................................................................................................................81
10.1
DATA HANDLING AND RECORD KEEPING....................................................................................81
10.2
QUALITY CONTROL AND QUALITY ASSURANCE..........................................................................82
11
ADMINISTRATIVE ASPECTS............................................................................................................82
11.1
ETHICAL ASPECTS .......................................................................................................................82
11.1.1
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) and 
Regulatory Authorities..................................................................................................82
11.1.2
Declaration of Helsinki/Good Clinical Practice ...........................................................83
11.1.3
Patient Information and Informed Consent ..................................................................83
11.1.4
Data and Safety Monitoring..........................................................................................84
11.1.5
Personal Data Protection...............................................................................................84
11.2
AUDITS AND INSPECTIONS...........................................................................................................85
11.3
STUDY MONITORING ...................................................................................................................85
11.4
STUDY DOCUMENTATION............................................................................................................85
11.4.1
Change in Protocol........................................................................................................86
11.4.2
Site Initiation Visit/Investigator Meeting .....................................................................86
11.4.3
Source Document..........................................................................................................86
11.4.4
Recording of Data on Electronic Case Report Form (eCRF).......................................86
11.4.5
Investigator Site File.....................................................................................................87
11.4.6
Clinical Study Supplies.................................................................................................87
11.5
DATA MANAGEMENT ..................................................................................................................87
11.6
STUDY COMPLETION....................................................................................................................88
11.7
CLINICAL STUDY REPORT............................................................................................................88
11.8
DISCLOSURE ................................................................................................................................88
11.9
RECORDS .....................................................................................................................................88
11.10
FINANCING AND INSURANCE .......................................................................................................89
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12
REFERENCES........................................................................................................................................90
13
APPENDICES .........................................................................................................................................94
APPENDIX A
DRUGS WITH RISK OF TORSADES DE POINTES...........................................94
APPENDIX B
CYP3A4 GUIDANCE.................................................................................................95
APPENDIX C
SUMMARY OF RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) V1.1......................................................................................................................96
APPENDIX D
QUALITY OF LIFE - EORTC QLQ-C30 .............................................................100
APPENDIX E
COUNTRY-SPECIFIC REQUIREMENTS ..........................................................102
APPENDIX F
PROTOCOL AMENDMENT HISTORY AND SUMMARY OF 
CHANGES
106
AMENDMENT 2 (V3.0); 20 DECEMBER 2019..............................................................................................106
PRIOR AMENDMENTS....................................................................................................................................109
List of Tables
Table 1
Schedule of Activities (SoA)............................................................................................................13
Table 2
Imaging Guidelines...........................................................................................................................40
Table 3
ECOG Performance Status ...............................................................................................................43
Table 4
Biomarker Blood Sample Collection................................................................................................46
Table 5
Investigational product .....................................................................................................................47
Table 6
Dose Modification Criteria for AL101.............................................................................................51
Table 7
Adverse Event Observation Periods.................................................................................................67
Table 8
Definition of Adverse Events Intensity According to NCI-CTCAE v5.0........................................69
Table 9
WHO-UMC Adverse Events Causality Criteria...............................................................................69
Table 10
Colitis Management..........................................................................................................................73
Table 11
Modified MD Anderson (MDA) Criteria for Bone Metastases+ .....................................................99
List of Figures
Figure 1
Effect of AL101 on Tumor Growth in Mice Bearing ACC PDX Tumors*.....................................28
Figure 2
Algorithm for p-DILI identification and mandatory SAE reporting in patients with - (i) 
normal baseline liver biochemistry, and (ii) abnormal baseline liver biochemistry.........................75
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GLOSSARY
Abbreviation/Term
Definition
ACC
Adenoid Cystic Carcinoma
ADL
Activity of Daily Living
AE
Adverse Event
AESI
Adverse Event(s) of Special Interest
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area under the curve
BMI
Body Mass Index 
BUN
Blood Urea Nitrogen 
C1D1
Cycle 1, Day 1
CBC
Complete Blood Count
CI
Confidence Interval
CNS
Central Nervous System
CR
Complete Response
CrCl
Creatinine Clearance
CRO
Contract Research Organization
CT
Computerized Tomography
CTCAE
Common Terminology Criteria for Adverse Events (version 5.0)
DILI
Drug-induced liver toxicity
DLT
Dose limiting toxicity
DMC
Data Monitoring Committee 
DOR
Duration of Response
ECG
12-Lead Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture 
EORTC-QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire 30 questions
EOS
End of Study
FDA
Food and Drug Administration
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Abbreviation/Term
Definition
FFPE
Formalin-Fixed Paraffin Embedded
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GI
Gastrointestinal
GSI
Gamma-secretase inhibitor
HCV
Hepatitis C
HIPAA
Health Insurance Portability and Accountability Act 
HIV
Human Immunodeficiency Virus 
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation 
ICR
Independent Review Committee 
IEC
Independent Ethics Committee 
IHC
Immunohistochemistry 
IRB
Institutional Review Board
ITT
Intent-To-Treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
LC-MS/MS
Liquid Chromatography with Tandem Mass Spectrometry
LD
Longest Diameter
LDH
Lactate dehydrogenase
MDA
MD Anderson
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MYB
Myeloblastosis
NCI
National Cancer Institute
NCS
Not Clinically Significant
NGS
Next Generation Sequencing 
NICD
Notch Intracellular Domain 
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over the counter
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Abbreviation/Term
Definition
PD
Progression of Disease
PDX
Patient Derived Xenograft 
PET
Positron Emission Tomography
PFS
Progression Free Survival
PI
Principal Investigator
PK
Pharmacokinetics
PP
Per-Protocol 
PR
Partial Response
PSA
Prostate-specific Antigen
PT (AE)
Preferred Term
PT (lab)
Prothrombin Time
PTT
Partial Thromboplastin Time 
QW
Every week
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD (clinical)
Stable Disease
SD (statistics)
Standard Deviation
SoA
Schedule of Activities 
SOP
Standard Operating Procedure
SUSAR
Serious Unexpected Suspected Adverse Reaction 
TEAE
Treatment Emergent Adverse Event
TGI
Tumor Growth Inhibition
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
UMC
Uppsala Monitoring Centre
US
United States
WHO
World Health Organization
WMA
World Medical Association 
WOCBP
Women of Childbearing Potential 
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1
INTRODUCTION
1.1
THERAPEUTIC INDICATION
Adenoid cystic carcinoma (ACC) is a rare cancer most often occurring in the salivary glands 
with an incidence of 4.5 cases per million individuals (Lee, 2015; Moskaluk, 2013). The 
neoplasm can also arise in other locations, including the oropharyngeal and nasopharyngeal 
spaces, trachea, breast, lacrimal gland, skin, and lower female genital tract. ACC is characterized 
by an indolent but persistent course, with high rates of both local-regional recurrence and distant 
metastasis (Chae, 2015; Dillon, 2016; Ellington, 2012). Five, ten, and fifteen-year survival rates 
after surgical resection have been reported around 80%, 60%, and 45%, respectively, with almost 
half of patients dying from ACC, as opposed to other causes, at long-term follow-up (He, 2017; 
Lloyd, 2011).
Multiple studies have been conducted to discover genetic mutations and biomarkers specific for 
ACC (Ellington, 2012; Frierson, 2013). In addition to the frequent translocations involving 
myeloblastosis oncogene (MYB) in ACC, sequencing of tumor samples revealed genomic 
alterations in epigenetic modification (chromatin remodeling) pathway, DNA damage/ 
checkpoint pathway, FGF/IGF/PI3K signaling, and Notch signaling in a subset of patients (Ho, 
2013; Stephens, 2013). It was specifically demonstrated that NOTCH1 mutations significantly 
correlate with confirmed histology, advanced disease stage at diagnosis, higher incidence of liver 
and bone metastasis, and shorter relapse-free and overall survival (Ferrarotto, 2017; Sajed, 
2017).
1.2
CURRENT THERAPY
Most ACC primary tumors are treated with surgical resection and postoperative radiotherapy, yet 
local and repeated recurrences are common (Ellington, 2012). In advanced stage, conventional 
chemotherapy regimens are still utilized as first-line therapy although antitumor activity across a 
variety of chemotherapy classes is poor. Cisplatin and 5-FU or CAP (cisplatin, doxorubicin, and 
cyclophosphamide) regimens can be used as combination chemotherapy (Laurie, 2011; 
Papaspyrou, 2011). Agents commonly given as monotherapy include cisplatin, mitoxantrone, 
epirubicin, vinorelbine, paclitaxel, and gemcitabine. However, few of these agents have shown 
efficacy, highlighting the need for new therapeutic options (Chae, 2015; Ellington, 2012; Ko, 
2016). To date, no agent has been formally tested in ACC tumors that harbor Notch activation.
1.3
INVESTIGATIONAL THERAPY
AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling. The 
drug product is a single-use sterile solution (1.2 mg/mL) for intravenous (IV) administration.
Notch receptors are highly conserved, Type I transmembrane glycoproteins that regulate critical 
cellular functions, including differentiation, proliferation, self-renewal, survival, and cell fate 
determination. The Notch protein family has 4 members (Notch 1 to Notch 4) in mammals. 
Mammalian Notch receptors are activated by 4 transmembrane-bound ligands (Jagged1, 
Jagged2, Delta1, and Delta4 homologs) (LaFoya, 2016).
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The Notch signaling pathway relies on regulated proteolysis. Upon ligand binding to the Notch 
receptor, a series of steps leads to cleavage by gamma secretase within the transmembrane 
domain. This frees the Notch intracellular domain (NICD), which translocates to the nucleus to 
form a transcriptional activation complex with the DNA-binding factor CSL (CBF1/Suppressor 
of Hairless/Lag1) and coactivators belonging to the mastermind-like family of proteins. Thus, a 
gamma-secretase inhibitor (GSI) such as AL101 can block the final step in Notch activation, the 
formation of the NICD.
1.3.1
Nonclinical Studies
The comprehensive battery of non-clinical studies conducted with AL101 included 
pharmacology studies, pharmacokinetic and metabolism studies in multiple species, and toxicity 
studies in rats and dogs.
In nonclinical models, AL101 exhibited antitumor/antiangiogenic activities including inhibition 
all 4 mammalian Notch receptors (Notch1 to Notch4) with high and equal potency. AL101 
exhibited broad-spectrum in vivo antitumor activity in nonclinical human cancer xenograft models 
of diverse histological types, including T-cell acute lymphoblastic leukemia and breast, non-small 
cell lung, pancreatic, and colorectal carcinoma, among others. AL101 exerted its antitumor activity 
through direct inhibition of cell proliferation and indirectly via inhibition of tumor angiogenesis.
In vitro genetic toxicity and safety pharmacology studies and in vivo single- and repeat-dose (up 
to 5-weeks duration) IV toxicity studies in rats and dogs (including safety pharmacology 
endpoints), were performed to evaluate the potential toxicologic profile of AL101. Collectively, 
the non-clinical toxicology studies have established a dose- and concentration-dependent safety 
profile for AL101 and its active metabolite, with effects that are primarily attributed to 
target-mediated Notch inhibition.
More detailed information is available in the AL101 Investigator’s Brochure (IB).
1.3.2
Clinical Studies
The clinical development program for AL101 in cancer patients include:

Study CA216001 evaluated patients with advanced solid tumors who were treated 
with AL101 monotherapy; the study was designed as ascending multiple-dose 
study (completed on 22 June 2017, study report in progress).

Study CA216002 evaluated patients with T-cell acute lymphoblastic leukemia or 
lymphoma who were treated with AL101 in combinations with dexamethasone 
(completed, study report pending).

Study CA216003 evaluated patients with advanced solid tumors who were treated 
with AL101 in combination with 3 different standard-dose chemotherapy 
regimens (paclitaxel, carboplatin-paclitaxel, and fluorouracil-leucovorin-
irinotecan [FOLFIRI]) (completed, study report pending).

Ongoing ACCURACY study (preliminary results).
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In Study CA216001, 94 patients were treated with AL101 (BMS-90692), of whom 83 patients 
received AL101 on a weekly (QW) schedule at doses ranging from 0.3 mg to 8.4 mg, and 11 
patients receiving AL101 every 2 weeks (Q2W schedule) at doses of 4 mg or 6 mg. The mean 
half-life (SD) following multiple-dose administration of AL101 over the 0.3-mg to 8.4-mg dose 
administered QW for at least 4 weeks ranged from 67.4 (18.7) hours to 147.8 (154.1) hours, 
indicating that AL101 is slowly eliminated. The most common reason given for discontinuation 
of treatment was disease progression, which was reported for 66 (70.2%) of patients in the study. 
Median duration of exposure was 5.9 weeks (range: 1 to 238 weeks) for the overall study 
population.
The primary endpoint was safety and establishment of recommended dose for Phase 2. Clinical 
safety data from Study CA216001 (N = 94) indicate that AL101 is tolerated at weekly doses of 
0.3 mg to 4 mg. Dose limiting toxicities (DLTs) were observed in the 6 mg dose level in 2 
patients (Grade 3 vomiting/Grade 3 lipase elevation and Grade 3 diarrhea) and 8.4 mg dose level 
in 3 patients (Grade 5 liver failure, recurrent Grade 3 hypersensitivity reaction and Grade 3 
vomiting, each of which occurred after 2 doses of AL101). The maximum tolerated dose (MTD) 
was defined as 4 mg for a QW dosing schedule and 6 mg for a Q2W dosing schedule (for more 
on dose selection details refer to Section 1.4.1). Most AEs have been Grade 1 or 2. The Grade 3 
to 4 related AEs occurring in at least 2 patients (out of 94) included hypophosphatemia (33 
patients, 35.1%)), diarrhea (18 patients , 19.1%)), hypokalemia (6 patients, 6.4%)), vomiting (4; 
patients, 4.3%)), aspartate aminotransferase increased (3 patients, 3.2%), dehydration (2 patients, 
2.1%), and hyponatremia (2 patients, 2.1%).
Best overall response assessed by the Investigator based on Response Evaluation Criteria In 
Solid Tumors criteria (RECIST) v1.1 showed preliminary evidence of AL101 clinical activity in 
2 metastatic ACC patients bearing NOTCH1 mutation who were treated with AL101 4 mg IV 
infusion once per week (QW) as follows:

First patient (63 years old male) had confirmed partial response (PR) with 
progressive disease at 8 months. Change from baseline in target lesion was 
23% decrease on Day 50 (8 weeks), 39% decrease on Day 113 (16 weeks), 
and 41% decrease on Day 162 (24 weeks).

Second patient (66 years old female) had stable disease at the first on-
treatment assessment: 2 mm decrease (5.7%) in target lesion on Day 53/8-
week assessment. Patient received 4 mg QW and at day 44 changed to 2.4 
mg QW; she discontinued treatment due to a non-treatment-related AE (at 
day 106).
In Study CA216002, preliminary evidence of clinical activity was observed in 3 patients, 2 with 
complete remission (resulting in allogeneic transplantation in 1 patient and ongoing >17 months 
in the other patient) and 1 patient with partial remission that lasted approximately 12 weeks, all 
at the 6 mg dose level (n = 20). In addition, previous data (December 2014) showed evidence of 
clinical activity (≥ 50% reduction in bone marrow blast percentage) in 8 (32%) of 25 patients, 
including 4 patients treated at the 4 mg dose and 4 patients treated at the 6 mg dose. On a weekly 
schedule, the 6-mg dose was tolerated in this population, and the expansion cohort was opened at 
this dose level.
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In Study CA216003, for the more common tumor types, confirmed objective responses were 
reported for 8 of the 22 patients (36.4%) with TNBC (1 patient with a CR and 7 patients with 
PR) and 5 of the 19 patients (26.3%) with NSCLC (all with a PR). The most frequently reported 
AEs (>50% of all treated patients), regardless of causality, were fatigue, diarrhea, 
hypophosphatemia, nausea, and decreased appetite. Although there were limited numbers of 
patients in some treatment groups, the frequency of AEs appeared to be generally similar during 
QW administration of AL101 at a dose of 4 mg (Arms A, B, C) or 6 mg (Arms A, C) across all 
chemotherapy treatments.
In the current ACCURACY study, preliminary results have been reported. As of the cut-off date 
of August 31, 2019, data from 18 patients is included in the Efficacy Evaluable Analysis set. 
Among the 18 patients who had at least one follow-up radiological examination, the investigator 
assessment of best response based on RECIST v1.1 or modified MDA bone response criteria was 
PR in 4 patients (22%), SD in 7 patients (39%) and PD in 7 patients (39%); disease control rate 
(PR+SD) was 61% (11 patients) (Ferrarotto, 2019). The longest response duration is over 5 
months and ongoing and the longest SD is over 7 months and ongoing. As of October 11, 2019, 
the safety analysis set included 29 patients. Overall, 23 patients reported at least 1 TEAE. 
CTCAE Grade 1 were reported by 3 patients (10.3%), Grade 2 by 6 patients (20.7%), Grade 3 by 
31% (9 patients); Grade 4 by 3 patients (10.3%) and Grade 5 by 2 patients (6.9%). The most 
frequently reported AEs (>30% of all treated patients), regardless of causality, were nausea, 
fatigue, diarrhea and vomiting. SAEs were reported for 14 patients (48.3%) with pneumonia 
reported by 3 patients (10.3), all other events were single incidences. Treatment-related SAEs 
included infusion site reactions (2 reactions in one patient) and keratoacanthoma (each, 1 patient, 
3.4%).
The observed safety profile of AL101 in the ACCURACY study to date suggests a lower rate of 
adverse events 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 6.6), the rate of Grade 3 
diarrhea was reduced to 3.4% vs. 19.1% in the ongoing ACCURACY study and study 
CA216001, respectively.
Based on results of study CA216001 for AL101 monotherapy, the previous developer 
recommended that the MTD for a QW dosing schedule was 4 mg, and for Q2W dosing schedule 
was 6 mg. In Study CA6216002 for AL101 monotherapy in T-ALL and T-LL, the prior 
developer concluded 6 mg QW was tolerated in that patient population. The previous developer 
decided to discontinue development of AL101 due to business reasons and not due to any safety 
concerns associated with the use of AL101.
This suggest that although the MTD in the solid tumor population treated on a QW dosing 
schedule was recommended by previous developer of AL101 to be 4 mg QW, however, with a 
rigorous control of GI toxicity as shown CA216002, a dose of 6 mg is safe to administer to 
patients suffering with advanced cancer.
For additional information please refer to AL101 IB.
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1.4
STUDY RATIONALE
AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling that is 
currently under development as an antitumor/antiangiogenic agent for single use or in 
combination with other targeted agents in the treatment of tumor growth and metastasis. A large 
body of experimental evidence supports the causal role of Notch pathway deregulation in 
tumorigenesis (Braune, 2016; Previs, 2015; Vinson, 2016; Wang, 2015; Xiao, 2016; Zhao, 
2017). In ACC, sequencing of tumor samples revealed genomic alterations in the Notch1 
pathway in a subset of patients with a distinct ACC phenotype. ACC patients with NOTCH1 
mutations have an aggressive disease with a distinct pattern of metastasis and worse prognosis 
(Ferrarotto, 2017). In addition to NOTCH1 mutations, other NOTCH mutations (2, 3, 4) were 
identified in ACC (Bell, 2014; Sant, 2017; Stoeck, 2014).
The effect of AL101 was evaluated in four ACC Patient Derived Xenografts (PDX) models that 
utilize tumors derived directly from patients have become the best platform for screening and 
predicting drug efficacy in oncology nonclinical models. These tumors, that are transferred 
directly to mice, without tissue culturing, maintain the histopathological and molecular features 
and best mimic the original human cancer (Izumchenko, 2017).
The effect of AL101 was evaluated prospectively in tumors with wild type Notch versus tumors 
with Notch activating mutations. Seventy milligrams of tumor tissue were implanted into 
Athymic Nude female mice 6-12 week old (Treatment arm N=5, Control arm N=10). 
Randomization to study arms was done once tumors reached a volume of 150-300 mm3. Dosing 
regimen was 7.5 mg/kg AL101 po weekly, 4 days on/ 3 days off. Tumor volumes were measured 
twice a week.
Tumor growth inhibition (TGI) was significantly higher with AL101 monotherapy, compared to 
vehicle in both Notch mutant models (ACCx9: 110% TGI P<0.0001; and ACCx11: 78% TGI 
P=0.0441). AL101 did not have a significant effect in models without Notch activating mutations 
(ACCx6: 37% TGI P>0.99; ACCx5M1: 60% TGI P=0.25 (Figure 1).
Figure 1
Effect of AL101 on Tumor Growth in Mice Bearing ACC PDX Tumors*
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* Dosing regimen was 7.5 mg/kg AL101 po weekly, 4 days on/ 3 days off.
Abbreviations: NS = not significant; PDX = patient-derived xenograft; TGI = tumor growth inhibition; WT = wild 
type
Based on a preliminary Phase 1 study with AL101 (CA216001) where clinical activity of AL101 
was shown in an unselected patient population with solid tumors (see Section 1.3.2), the current 
study is designed to evaluate the efficacy and safety of AL101 in patients with ACC bearing 
activating Notch mutations.
The preliminary results of this study (see Section 1.3.2) suggest that the patient population 
initially recruited into this study had advanced progression, more than expected based on 
literature review (Ferrarotto, 2017; Ho, 2019). Thus, with the addition of Cohort 2, the Sponsor 
will now evaluate the biological activity in a larger patient population to better understand the 
response rate and the nature of the response as well as define the patients who are likely to 
respond to the drug in future studies.
1.4.1
Dose Selection
The doses selected for this study, 4 mg QW (Cohort 1) and 6 mg QW (Cohort 2) are 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. Please also refer to the IB for further information.
In Study CA216001, in dose escalation on a QW schedule, patients were treated at AL101 dose 
levels of 0.3 (n = 4), 0.6 (n = 3), 1.2 (n = 4), 2.4 (n = 4), 4 (n = 7), 6 (n = 14), and 8.4 mg (n = 
11). In study CA216001, AL101 was safe and tolerated in doses up to 4 mg QW administration. 
DLTs were observed in the 6 mg and 8.4 mg dose levels. As AL101 potentially contributed to 
these DLTs and no DLTs were reported in the 7 DLT-evaluable patients treated at this dose in 
the dose escalation phase, the MTD in the solid tumor population treated on a QW dosing 
schedule as was recommended by the previous developer of AL101 to be 4 mg.
Overall, 43 patients were treated at a dose of 4 mg QW, in either the dose escalation (N=7) or 
dose expansion (N=36) phases. Treatment-related ≥Grade 3 AEs included hypophosphatemia 
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(41.9%; 18/43), diarrhea (18.6%; 8/43), hypokalemia (7.0%; 3/43), and anaphylactic reaction, 
anemia, AST increased, nausea, pruritus, and vomiting (2.3% each; 1/43).
PK results from Study CA216001 indicate that AL101 exposure (Cmax and AUC) increases 
approximately linearly for QW dosing from 4 mg to 6 mg.
PD results (Hes1 expression in PB) from Study CA216001 indicate greater maximum effect and 
duration of target inhibition when increasing the QW dose from 4 mg to 6 mg. Mean Hes1 
inhibition is maintained greater than 50% throughout 7 day period at 6 mg, where it recovers to 
under 50% by day 7 at 4 mg.
Based on the observed safety profile of AL101 in this study to date (see Section 1.3.2), the 
existing toxicity management guidelines (outlined in Section 6.6) for GI and liver toxicity (liver 
function test to be monitored weekly; refer also to Sections 8.4.1 and 8.4.5 for liver-related 
adverse event of special interest) and the totality of the data from all 3 Phase 1 studies (see 
Section 1.3.2) as well as the enhanced PD modulation at 6 mg QW, the Sponsor decided to add a 
cohort with AL101 dose of 6 mg QW (Cohort 2); this dose may offer patients an increased 
benefit (as evident by PK/PD data described above) while maintaining their safety with weekly 
visits and rigorous toxicity management guidelines. Notably, using the toxicity management 
guidelines for GI adverse events, the rate of Grade 3 diarrhea was reduced to 3.4% in the 
ongoing ACCURACY study.
2
STUDY OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess the clinical activity of 
AL101 (BMS-906024) using 
radiographic assessments and 
RECIST v1.1 in ACC patients with 
activating Notch mutations

Objective response rate (ORR; CR and PR) 
by RECIST v1.1 as determined by 
Investigator review. For patients with bone-
exclusive disease, the modified MDA bone 
criteria will be used to access response (see 
Table 11).
Note: Investigator review will be done in 
accordance to FDA “Clinical Trial Imaging 
Endpoint Process Standards Guidance for 
Industry” (April 2018).4
Secondary

Clinical activity assessments

Duration of response (DOR) by 
Investigator review based on RECIST v1.1.
4 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm268555.pdf
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
Progression free survival (PFS) by 
Investigator review based on RECIST v1.1.

Overall survival (OS).

To assess quality of life (QoL) in ACC 
patients with activating Notch 
mutations

Change from baseline in EORTC 
QLQ-C30.

To confirm safety and tolerability of 
AL101 in ACC patients with activating 
Notch mutations

Frequency, duration and severity of adverse 
events (AEs) and serious adverse events 
(SAEs).

Incidence of clinically significant 
laboratory abnormalities; safety laboratory 
evaluations includes complete blood count 
(CBC), blood biochemistry and urinalysis.

To obtain a set of population 
parameters and to identify covariates 
that affect systemic exposure to AL101 
and metabolite(s).

A population (mixed-effects) PK approach 
will be used to analyze the concentration 
data.
For AL101 and metabolite(s), one- and two-
compartment linear models will be applied to 
the data.
Exploratory

To establish correlation between 
positive Notch1 intracellular domain 
(NICD1) stain and Notch1 activating 
mutations.

To establish the correlation between 
mutations in Notch and associated 
genes and response or resistance to 
investigational product.

Predictive biomarkers of response or 
resistance to the investigational product will 
be explored:

Immunohistochemistry (IHC): Tumor 
specimens will be stained for NICD1 
and other biomarkers such as, but not 
limited to: programmed death ligand 
(PD-L1), Ki-67 and FBXW7.

Next Generation Sequencing (NGS): 
Mutational analysis will be performed in 
tissues samples as well as in cell-free 
DNA cfDNA.

Pharmacodynamic markers indicative of 
drug activity will be measured, including 
HES-1 and others such as but not limited 
to: HES-4, HES-5, HEY-1, 2, HEYL, HIF1 
alpha, and others.
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3
STUDY DESIGN 
This is a Phase 2, non-comparative, open-label, multicenter study of AL101 in patients with 
recurrent or metastatic ACC who harbor NOTCH 1,2,3,4 activating mutations.
The study includes 2 cohorts, ran in a sequential fashion:

Cohort 1 – AL101 4 mg once weekly (QW) intravenously (IV)

Cohort 2 – AL101 6 mg QW IV
Cohort 1 will continue to enroll to reach up to a maximum of 45 patients. Cohort 2 will open for 
enrollment up to a maximum of 42 patients. Prior to entering the study, to determine eligibility, 
potential candidates will undergo pre-screening assessment and confirmation for the presence of 
activating Notch mutations. Available mutation status from prior tests with any commercially 
available or locally developed NGS assay are acceptable. In Europe any commercially available 
CE marked device shall be used (for country specific requirements refer to Appendix E.
If historical genotyping results are not available, testing will need to be conducted during pre-
screening using a laboratory developed or commercially available NGS assay to identify and 
confirm an activating Notch mutation. Any newly characterized mutation (such as tandem 
duplication, variant allele frequency, variants of unknown significance, etc.), will be evaluated 
with the Sponsor on a case-by-case basis. Pre-screening study-specific assessments may be done 
while potential candidates are on other therapy provided that a separate pre-screening informed 
consent form is signed.
Patients with activating Notch mutations will then undergo screening assessments to determine 
study eligibility over a 28-day Screening period. Enrollment of patients with bone exclusive 
disease should be discussed and approved by the Sponsor’s Medical Monitor before enrollment 
(refer to inclusion criterion 5 in Section 4.1). For all patients, prior treatments and responses to 
such treatments, including radiological images and reports, within a year of study entry will be 
collected as part of the medical history; for patients who are currently enrolled, this information 
will be collected retrospectively.
Starting on Cycle 1, Day 1, eligible patients will receive AL101, either 4 mg QW IV in Cohort 1 
or 6 mg QW IV in Cohort 2, on Days 1, 8, 15, and 22 of each 28-day cycle until disease 
progression, unacceptable toxicity, or consent withdrawal. For patients with radiological 
progression, investigational product may be continued as long as the patient is having clinical 
benefit, is agreed to by the patient and physician and approved by the Sponsor’s Medical 
Monitor. 
Paired tumor biopsies will be collected at screening (fresh or archival5 within 3 years) and on-
treatment at Cycle 4 Day 1 ±28 days provided medically safe and not contraindicated. Samples 
will be sent to a central vendor for NGS analysis. Tumor Formalin-fixed paraffin embedded 
5 If an archival tumor block or 25 unstained slides are not available, the patient will be required to have a fresh 
tumor sample obtained at screening.
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(FFPE) slides will be evaluated by IHC for NICD1 stain. On the day of the on-treatment biopsy, 
blood will also be drawn for PK and biomarker assessments.
During the Treatment period, patients will undergo radiographic assessments every 8 weeks 
(±3 days) for review by the Investigator. Scans will be collected and held for possible future 
retrospective evaluation by ICR. Other assessments will be done as specified in Schedule of 
Activities (SoA; Table 1), including safety and exploratory biomarkers.
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.
All patients will undergo end of study (EOS) visit 30 days post last treatment and be contacted 
by phone every 3 months to determine survival status. In patients who discontinued 
investigational product due to toxicity, radiographic imaging will be done every 3 months until 
disease progression or until patient initiates another anti-cancer therapy.
Study participation for each patient consists of:
Screening period: 
up to 28 days 
Treatment period: 
Weekly treatment, until disease progression6, unacceptable 
toxicity, or consent withdrawal
EOS: 
30 days after the last administration of investigational product. 
Long term follow-up: 
Every 3 months.
6 For patients with radiological progression, investigational product may be continued as long as the patient is 
having clinical benefit, is agreed to by the patient and physician and approved by the Sponsor’s Medical Monitor.
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4
STUDY POPULATION
4.1
INCLUSION CRITERIA
In order to be eligible for participation in this study, the patient must meet all of the following:
Age
1.
Age >18 years old.
Type of Patient and Disease Characteristics
2. Histologically confirmed ACC with known NOTCH 1/2/3/4 activating mutation that is 
recurrent or metastatic, not amenable to potentially curative surgery or radiotherapy.
3. Evidence of radiographic or clinical disease progression within 6-months of signing informed 
consent; newly diagnosed metastatic patients will be allowed.
4. Patients must have FFPE tissue available (please refer to Laboratory Manual for number of 
slides required). Archived7 (within 3 years) or fresh core or punch needle biopsied are 
acceptable.
5. Must have at least 1 target lesion that is measurable per RECIST v1.1 for patients with nodal 
or visceral metastasis. Patients with bone exclusive disease will also be eligible after 
consultation and approval with Sponsor’s Medical Monitor and only if bone lesions are 
evaluable and measurable by CT or MRI as per modified MDA Criteria. (see Table 11 in 
Appendix C).
6. Resolution of clinically significant toxicities related to prior therapy to National Cancer 
Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE v5.0) 
≤ Grade 1, except for sensory neuropathy with resolution to ≤ Grade 2 and alopecia.
Sex
7. Male and/or Female.
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies (refer to Section 7.3 on 
contraception). Refer to Appendix E for country-specific requirements on contraception 
language.
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 investigational product. An extension up to 72 hours is permissible in situations 
where results cannot be obtained within the standard 24-hour window. 
9. WOCBP must agree to follow method(s) of contraception for the duration of the treatment 
with AL101 plus post-treatment completion based on country-specific requirements. Refer 
to Appendix E for country-specific requirements on contraception language.
7 If an archival tumor block or 25 unstained slides are not available, the patient will be required to have a fresh 
tumor sample obtained at screening.
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10. Men who are sexually active with WOCBP must agree to method(s) of contraception for the 
duration of treatment with AL101 plus post-treatment completion based on country-specific 
requirements. Refer to Appendix E for country-specific requirements on contraception 
language.
Informed Consent
11. Capable of giving signed informed consent which includes compliance with the requirements 
and restrictions listed in the informed consent form (ICF) and in this protocol.
4.2
EXCLUSION CRITERIA
The patient must be excluded from participating in the study if meet any of the following:
Medical Conditions
1.  Diagnosed with a malignancy in the past 2 years. However, patients with the following 
diagnoses may enroll as long as there is no current evidence of disease:
a.
Non-melanoma skin cancers
b. Melanoma in situ,
c.
Localized cancer of the prostate with current prostate-specific antigen of <0.1 ng/mL,
d. Treated thyroid cancer,
e.
Treated cervical carcinoma in situ
f.
Treated ductal/lobular carcinoma in situ of the breast.
2. Current or recent (within 2 months of investigational product administration) gastrointestinal 
disease such as disorders that increase the risk of diarrhea, such as inflammatory bowel 
disease. Non-chronic conditions (e.g., infectious diarrhea) that are completely resolved for at 
least 2 weeks prior to starting investigational product are not exclusionary.
3. Evidence of uncontrolled, active infection, requiring systemic anti-bacterial, anti-viral or 
anti-fungal therapy ≤7 days prior to administration of investigational product such as known 
active infection with hepatitis B, hepatitis C (HCV), or human immunodeficiency virus 
(HIV) at Screening (e.g., positive HIV, HBsAg, HCV RNA at screening).
4.  Symptomatic central nervous system (CNS) metastases. Patients with asymptomatic CNS 
metastases as well as those with previously treated CNS metastases are eligible for 
enrollment in the study if at least four weeks has elapsed since last whole brain radiation 
treatment or at least two weeks has elapsed since last focal radiation treatment, steroid 
therapy is not required, and the patient is deemed clinically stable by the Investigator.
5. 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 patient associated 
with his or her participation in the study.
6. Female patients who are pregnant or breastfeeding.
Prior/Concomitant Therapy
7. Completed palliative radiation therapy < 7 days prior to initiating investigational product.
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8. Prior treatment with gamma secretase inhibitors. Prior treatment with anti-Notch antibodies 
may be allowed upon discussion with the Sponsor’s medical monitor.
9. Last chemotherapy, biologic, or investigational therapy agent <4 weeks or 5 half-lives 
(whichever is shorter) prior to initiating investigational product; 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.
Diagnostic Assessments
10. Eastern Cooperative Oncology Group (ECOG) performance status ≥2.
11. Abnormal organ and marrow function defined as:
a.
neutrophils <1500/mm3,
b. platelet count <100,000/mm3,
c.
hemoglobin <9 g/dL,
d. total bilirubin >1.5upper limit of normal (ULN) (except known Gilbert’s 
syndrome),
e.
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >2.5ULN 
OR >5ULN for patients with liver metastases,
f.
serum creatinine > ULN and creatinine clearance <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.
Other Exclusions
14. 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.
15. Life expectancy of less than 3 months.
16. Inability to be venipunctured and/or tolerate venous access.
17. Hypersensitivity and/or history of allergy to AL101 and any of its excipients.
4.3
PATIENT IDENTIFICATION
Each patient who signed informed consent will be assigned a patient 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 patient has signed the main informed consent form 
(ICF), the Investigator will enter the patient into the Screening section of the electronic case 
report form (eCRF). 
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4.4
SCREENING FAILURES
Patients who fail to meet the entrance criteria at any time during the Screening period are defined 
as screen failures. All screen failures will be recorded on the screening failure log, which 
documents the site number and screening number and reason(s) for screen failure. The screening 
failure log will be kept in the Investigator’s Site File.
Re-screening/re-assessment outside the Screening period will be possible on a case-by-case basis 
following Sponsor approval. Patients allowed to be re-screened will be assigned a new screening 
number (with referral in eCRF to the previous screening number); such patients will be 
determined a screen failure after the second screening confirmed the patient is ineligible.
4.5
EARLY WITHDRAWAL OF PATIENTS FROM THERAPY OR ASSESSMENT
Patients are free to discontinue their participation in the study at any time and without prejudice 
to further treatment. The Investigator must withdraw any patient from the study if that patient 
requests to be withdrawn, or if it is determined that continuing in the study would result in a 
significant safety risk to the patient.
Discontinuation or interruption of investigational product does not represent withdrawal from the 
study. Patients may withdraw or be withdrawn from investigational product at any time.
Patients who permanently discontinue investigational product or are withdrawn from the study 
for non-safety reasons prior to the first efficacy endpoint (i.e., upon 2 cycles of treatment) may 
be replaced.
Dosing of investigational product must be interrupted for any serious adverse reactions assessed 
by the investigator as related to investigational product. 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. 
Please refer to Section 6.6 for AL101 dose modifications and toxicity management which may 
lead to investigational product discontinuation. Pregnancy is a mandatory criterion for permanent 
discontinuation of investigational product. Any patient being managed with dose interruption for 
toxicity should have their study assessments followed per SoA.
The patient’s participation in the study may be discontinued due to the following reasons:

Request of Investigator

Life-threatening event or death

Patient withdrew consent

Patient is lost-to-follow-up
The patient may discontinue investigational product due to the following reasons:

Request of the Investigator

Adverse event

Treatment failure

Patient is non-compliant with study procedures or study protocol
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
Request of Sponsor or regulatory authority

Pregnancy

Other (to be specified in the electronic case report form; eCRF)
4.6
HANDLING OF WITHDRAWALS
If a patient is withdrawn from the study, every effort should be made to determine the reason. 
This information will be recorded on the patient’s eCRF. Patients who withdraw from the study, 
regardless of cause, should undergo all EOS assessments as specified in Schedule of Activities 
(SoA; Table 1). Follow-up visits will be scheduled, per protocol.
Patients will be asked to agree to be followed up as stated in the protocol regardless of the reason 
for discontinuation.
4.7
SPONSOR'S TERMINATION OF STUDY
The Sponsor reserves the right to discontinue 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 investigational product;

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.
5
STUDY PROCEDURES

Study procedures and their timing are summarized in SoA in Table 1.

No protocol-related procedures should be performed before patients provide written informed 
consent.

Procedures conducted as part of the patient’s routine clinical management 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.

Study-related events and activities including specific instructions, procedures, concomitant 
medications, dispensing of investigational products, and descriptions of AEs should be 
recorded in the appropriate source documents and eCRF.

Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patients should continue or discontinue study 
intervention.

Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
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
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The investigator will maintain a screening log to record details of 
all participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.

For patients who discontinue study therapy early for the reasons specified in Section 4.5, an 
End of Study (EOS) visit will be conducted as specified in SoA (Table 1). Other procedures 
and evaluations will be completed as deemed necessary by the Investigator.

For the long-term overall survival status assessment, patients and/or their caregivers will be 
contacted by phone every 3 months after EOS visit until death, patient withdraws consent or 
Sponsor terminates the study.

An unscheduled visit may be performed throughout the study at the patient’s request or as 
deemed necessary by the Investigator. The date and reason for the unscheduled visit will be 
recorded. The Investigator will monitor AEs and record concomitant medications. Other 
procedures and evaluations will be completed as the Investigator deems necessary; they may 
include (but are not limited to) safety laboratory tests, ECG, vital signs and physical 
examination.
5.1
EFFICACY ASSESSMENTS
5.1.1
RECIST v1.1
The primary efficacy endpoint, ORR, will be evaluated using RECIST v1.1 (Eisenhauer, 2009) 
as described in Appendix C (For patients with bone-exclusive disease, the modified MDA bone 
criteria will be used to access response; see Table 11 for response criteria for bone metastases). 
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 sent to 
central imaging for possible future reads.
The central imaging read is being conducted for regulatory purposes only. The Investigator is 
responsible for diagnostic and treatment decisions concerning their patients.
The process for image collection and transmission to the ICR during the study can be found in 
the Imaging Manual.
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 2.
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Table 2
Imaging Guidelines
Study Period
Schedule
Imaging (RECIST 1.1)
Imaging (MDA)
Screening
Within 28 days 
prior to day 1
At screening, the following image scans are required: 
1.
MRI of brain
2.
CT of Neck
3.
CT of Chest
4.
CT of Abdomen and
5.
CT of Pelvis  
For bone disease only patients, the 
following anatomic regions on MRI are 
required at ALL timepoints to assess 
osseous metastatic burden:
1.Skull (usually included in MR Brain)
2.Cervical Spine
3.Thoracic Spine
4.Lumbar Spine
5.Pelvis
6.Rib Cage (shoulders to be in field of 
view)
Treatment
Every 8 weeks 
(± 3 days) until 
disease 
progression
Follow up scans at 8-week intervals, the following image scans 
are required:
1. MRI of the brain for known or suspected disease
2. CT of Neck
3. CT of Chest
4. CT of Abdomen
5. CT of Pelvis required for known or suspected disease in the 
abdomen to ensure complete anatomic coverage of tumor 
burden. CT of the pelvis is preferred if there is suspected 
disease in the pelvis
Same as screening visit 
End of Study 
(EOS) Visit
30 days post last 
investigational 
product (± 7 
days)
At EOS the following image scans are required:
1. MRI of the brain for known or suspected disease
2. CT of Neck
3. CT of Chest
4. CT of Abdomen
5. CT of Pelvis required for known or suspected disease in the 
abdomen to ensure complete anatomic coverage of tumor 
burden. CT of the pelvis is preferred if there is suspected 
disease in the pelvis
Same as screening visit
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Study Period
Schedule
Imaging (RECIST 1.1)
Imaging (MDA)
Long-Term 
Follow-up
Every 3 months 
(± 7 days)
At Long-Term Follow-up the following image scans are required:
1. MRI of the brain for known or suspected disease
2. CT of Neck
3. CT of Chest
4. CT of Abdomen
5. CT of Pelvis required for known or suspected disease in the 
abdomen to ensure complete anatomic coverage of tumor 
burden. CT of the pelvis is preferred if there is suspected 
disease in the pelvis
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. MRI of the brain for known or suspected disease
2. CT of Neck
3. CT of Chest
4. CT of Abdomen
5. CT of Pelvis required for known or suspected disease in the 
abdomen to ensure complete anatomic coverage of tumor 
burden. CT of the pelvis is preferred if there is suspected 
disease in the pelvis
Same as screening visit
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5.1.2
Patient Reported Outcome: European Organization for Research and Treatment 
of Cancer Quality of Life Questionnaire 30 questions (EORTC QLQ-C30)
The EORTC QLQ-C30 will be administered during the study at screening and then every 4 weeks 
before investigational product administration.
EORTC QLQ-C30 was developed as an instrument to measure cancer patients’ 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 head and neck cancer (Bjordal, 2000; Chaukar, 2005).
The example of the English version of the EORTC QLQ-C30 can be found at Appendix D and at 
this link:
https://www.eortc.org/app/uploads/sites/2/2018/08/Specimen-QLQ-C30-English.pdf 
5.2
SAFETY ASSESSMENTS
Planned time points for all safety assessments are provided in the SoA (Table 1).
5.2.1
Adverse Events
Adverse events (AEs) will be assessed and recorded at all study visits throughout the study from 
informed consent signing through EOS visit (30 days following cessation of investigational 
product) (see Section 8.1).
5.2.2
Adverse Events of Special Interest
Adverse event of special interest (AESI) will be assessed and recorded at all study visits 
throughout the study from baseline through EOS visit (30 days following cessation of 
investigational product). For details see Section 8.4.
5.2.3
Medical History and Concomitant Medications
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 ACC.
Abnormal physical examination finding and/or the diagnosis of concomitant disease resulting 
from assessment at Screening must also be documented in the medical history section.
Information on all interventions (systemic therapy, surgery, radiation treatment) related to the 
patient’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.
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 investigational product must be recorded onto the eCRF 
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from the patient’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. Refer to Section 7.1 for prohibited and allowed medications.
5.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Status
The Eastern Cooperative Oncology Group (ECOG) Performance Status will be used to assess 
patients’ performance status (Table 3).
Table 3
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 house work, 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
5.2.5
Vital signs
Vital signs 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 investigational product and findings that worsen significantly, which meet the 
definition of an AE must be recorded on the AE eCRF.
5.2.6
ECG
Single 12-lead ECG will be obtained using a centrally provided calibrated ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. Triplicate 
ECGs, at least 3 minutes apart, will be performed if QTcF is > 500 msec or if the Investigator 
identifies an ECG finding (for example QT interval prolonged or cardiac arrythmia) that is an 
adverse event and related to investigational product. Additional timepoints may be added, as 
clinically indicated.
Patients should be in the supine position after the patient has rested for at least 5 minutes. In the 
event of possible ECG findings, additional ECG reads could be added at follow-up visits. The 
ECG evaluation will be performed centrally. Clinically significant ECG abnormalities will be 
recorded on the eCRF.
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5.2.7
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 (Table 1).
Significant findings made after the start of investigational product 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 (Table 1).
5.2.8
Safety Laboratory Assessments
Safety laboratory assessments for this study are to be performed by local laboratory at times 
designated in the SoA Screening laboratory results may be used for C1D1 if conducted within 3-
7 days.
Findings that worsen significantly after the start of investigational product which meet the 
definition of an AE per the Investigator’s discretion must be recorded on the AE eCRF (refer to 
Section 8.1).
The laboratory evaluations will include, but not limited to:

Hematology/CBC including hemoglobin, hematocrit, platelet count, white blood 
cell (WBC) count, and absolute differential count

Peripheral blood lymphocytes subsets; this may include percent of B cells, T 
cells, NK cell, T-Helper cells, T cytotoxic (killer) cells, T reg (suppressor) cells 
and macrophages. Blood will be collected and analyzed locally per available flow 
panels. Sites are allowed to leave the eCRF blank for any subsets not included in 
their standard evaluation panel.

Serum chemistry: Glucose, blood Urea Nitrogen (BUN), creatinine, total 
bilirubin, albumin, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase, lactate dehydrogenase (LDH), 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.

Triglycerides

Hemoglobin A1c

Thyroid function: Thyroid stimulating hormone (TSH), total T3 and free T4

Coagulation assessment, including: prothrombin time (PT), and activated partial 
thromboplastin time (aPTT).

Serology: HIV, HBsAg, HCV RNA (qualitative).

Prostate-specific antigen (PSA) (male only)
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
Urinalysis (dipstick): pH, glucose, ketones, protein, specific gravity, bilirubin and 
evidence of infection; microscopic examination will be done when findings are 
abnormal.

Lipase – only for patients who experience ≥ Grade 2 diarrhea
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.
5.2.9
Pregnancy Test
Women of childbearing potential will have a urine or serum pregnancy test at timepoints 
designated in the SoA.
5.3
POPULATION PHARMACOKINETICS
Blood samples for population pharmacokinetics (PK) will be obtained at the times designated in 
the SoA, footnote q (Table 1). Start- and end-time for each investigational product infusion (and 
any interruptions) will be recorded in the eCRF. 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.
A population (mixed-effects) approach will be used to analyze the concentration data, the goal 
being to obtain a set of population parameters and to identify covariates that affect systemic 
exposure to each of the parent and metabolite. For each of parent and metabolite, one- and two-
compartment linear models will be applied to the data. If graphics suggest that these models are 
not appropriate, other models such as those including non-linearity with respect to dose and/or 
time will be evaluated. The relationship of pharmacokinetic parameters to body size will be 
evaluated systematically. Other covariates will be considered for inclusion in the model based on 
graphics. Models will be selected based on graphics and changes in the objective function. The 
analysis will be conducted with NONMEM software.
For more details on instructions for collecting PK samples, refer to the Study PK Manual.
5.4
BIOMARKERS
Notch mutational status from prior tests with any commercially available NGS assay kit or as 
assessed at enrollment by institutional NGS test will be confirmed centrally. In Europe any 
commercially available CE marked device shall be used (for country specific requirements refer 
to Appendix E.
A variety of biospecimens including tumor tissue and blood will be collected at the times 
designated in the SoA (Table 1) and Table 4 to perform IHC, NGS and cfDNA analysis in a 
central laboratory.
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Predictive biomarkers of response or resistance to the investigational product will be explored, 
including but not limited to:

IHC: Tumor specimens will be stained for the NICD1 and other biomarkers such 
as but not limited to PD-L1, Ki-67 and FBXW7.

NGS: Mutational analysis will be performed in tumor tissue samples as well as in 
cfDNA.

Pharmacodynamic biomarkers indicative of drug activity will be measured in  
blood such as but not limited to:
-
Genes regulated by Notch activity: HES-1, 5, 4, HEY-1, 2, HEYL, NRARP.
-
Angiogenesis biomarkers: HIF1 alpha, and VEGF.
-
Negative regulators: DTX1, FBXW7.
Tumor tissue for biomarker analysis will be required for study participation (block or 25 
unstained slides required). Tumor biopsies will also be taken  on-treatment at Cycle 4 Day 1 ±28 
days.
Samples may be stored according to local regulations following the last participant’s last visit for 
the study at a facility selected by the Sponsor to enable further analysis of biomarker responses 
to AL101.
The Laboratory Manual will provide details on biomarker sample collection.
Table 4
Biomarker Blood Sample Collection
Cycle
1
2
3
4
Odd1
EOS2
Day
1
2
8
22
29/1
22
1
22
Sample 
Type
Volume 
(mL)
Time
Pre3
+7 h
+24-
48 h
Pre
Pre
+7 h
+24-
48 h
Pre
Biopsy4
pre
cfDNA
10
X
 
X
X
X
X
X
mRNA
2.5
X
X
X
X
X
X
X
X
X
X
X
1Every additional odd cycle (starting Cycle 5)
2End of Study
3Pre-infusion
4To be obtain on same day as on-treatment biopsy (to be collected on Cycle 4, Day 1 ±28 days)
5.4.1
Stipulations for Tumor Biopsy
Patients must agree to provide two separate tumor biopsies, at screening and on-treatment at 
Cycle 4 Day 1 ±28 days (or earlier if the patient progressed). 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 patient. (If the only tumor 
accessible for biopsy is also the only lesion that can be used for RECIST v1.1 response 
evaluation, then the patient may be exempt from biopsy after discussion with the Sponsor). 
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Attempts should be made to biopsy lesions which are not considered to be “target lesions” per 
RECIST 1.1. criteria.  
6
INVESTIGATIONAL PRODUCT
6.1
INVESTIGATIONAL PRODUCT ADMINISTRATION
AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling. It will 
be administered as described in Table 5.
Table 5
Investigational product
Intervention 
Name
AL101 
Type 
Small Molecule
Dose 
Formulation
Solution for infusion
Unit Dose 
Strength(s)
mg/mL
Dosage Level(s)
1.2 mg/mL; 4 mg (Cohort 1) and 6 mg (Cohort 2)
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 +10 minutes are permitted. The connection between the 
tubing from the infusion pump to the patient 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
Cohort 1: Prior to IV administration, the drug product is diluted 3.3 mL (use 5mL 
syringe) in a 250 mL infusion bag of 0.9% Sodium Chloride Injection, USP 
(normal saline) or 5% Dextrose Injection, USP (D5W).
Cohort 2:  Prior to IV administration, the drug product is diluted 5.0 mL (use 
5 mL syringe) 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 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.
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Premedication
Instructions
As with any medication containing Cremophor, use premedication per the 
institution guidelines to reduce risk of infusion reactions. For any questions, 
please contact the Sponsor’s Medical Monitor.
Based on prior experience with Taxol (containing Cremophor)8; 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, premedication with H1- and H2-blockers (diphenhydramine and 
ranitidine or equivalents) or corticosteroids (refer to Section7.1.2) will be given.
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).
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 investigational product will be performed by Fisher Clinical Services.
All packaging and labeling operations for investigational product 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, lot number, 
storage conditions, and Sponsor name and address. 
Former Name(s) 
or Alias(es)]
BMS-906024
For pre-medication instructions, refer to Section Error! Reference source not found..
Additional information is provided in the AL101 Study Pharmacy Manual.
6.2
METHOD OF ASSIGNING PATIENTS
This is an open-label design, with all patients assigned sequentially to 1 of 2 cohorts and receive 
AL101 monotherapy. Cohort 2 will be open for enrollment at each center after the current 
amendment is approved and Cohort 1 enrolled up to a maximum of 45 patients.
6.3
DISTRIBUTION AND SHIPMENT OF THE INVESTIGATIONAL PRODUCT
For detailed information on the distribution and receipt of investigational product please refer to 
the Study Pharmacy Manual.
The investigational product will be shipped under appropriate conditions with temperature 
monitoring device. Upon arrival at the clinical investigation site, the study pharmacist or 
designated team member should examine the investigational product supplies and report any 
8 Taxol (paclitaxel) label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf 
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discrepancies in amounts received, damaged supplies or temperature excursion immediately as 
outlined in the Study Pharmacy Manual.
Each shipment of investigational product supplies for the study will be accompanied by a 
shipment form describing the contents of the shipment, acknowledgement of receipt and other 
appropriate documentation. The study staff will confirm the receipt of clinical supply and will 
return signed drug accountability logs as instructed in the Study Pharmacy Manual.
All study supplies should arrive at the Pharmacy/Investigational site in sufficient quantity and in 
time to enable dosing as scheduled. Investigational product shipment will be done according to 
enrollment projections.
6.4
STORAGE AND HANDLING OF THE INVESTIGATIONAL PRODUCT AT THE CLINICAL 
SITE
Please refer to the Study Pharmacy Manual for AL101 preparation. Each drug kit will be labeled 
with the protocol number, storage information, warning language (i.e., as required by local 
legislation for investigational drug products), dosing and storage instructions. Immediately 
before dispensing investigational product, the dispensing study staff member will write on the 
label the patient’s Study ID number.
The Investigator or the designated pharmacist (or other authorized designee) is responsible for 
ensuring that the appropriate storage conditions for the investigational products are maintained in 
accordance with the requirements in the Study Pharmacy Manual.
The study staff and monitors should also check the investigational product supplies to ensure 
sufficient amount of investigational product is on hand for active patients and that the supplies 
are not expired.
All investigational products must be kept in a locked area with access to the investigational 
product limited to designated study personnel. Only personnel under the supervision of either the 
Investigator or the local pharmacist are authorized to dispense investigational product. The 
Investigator is responsible for recording the receipt and use of all drugs supplied, and for 
ensuring the supervision of the storage and allocation of these supplies. Full accountability will 
be performed for all used and unused investigational product.
Investigational product should be stored as instructed per the IB.
6.5
ACCOUNTABILITY AND COMPLIANCE OF INVESTIGATIONAL PRODUCT
The Investigator or pharmacist/designee may dispense investigational product(s) for only 
patients enrolled in the study. Individual patient accountability records must be kept by the site 
staff. The patient number, the date, batch number/wallet number, and quantity of investigational 
product used or returned by the patient, as well as device and device components will be 
recorded on the appropriate accountability forms by the site staff. These records and the 
inventory of investigational product, device and device components on site will be verified by 
the study monitor for accuracy and completeness on an ongoing basis throughout the study. 
Unused drug supplies will be disposed of as instructed in the Study Pharmacy Manual.
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Treatment compliance will be assessed at all visits during the study. It will be based on 
accountability records and an inventory of used/unused supplies.
At the end of the study, the monitor will conduct a final drug reconciliation for all patients and 
the study site overall. All records of investigational product administration, accountability 
records and drug disposition records will be examined and reconciled by the study monitor. 
Further details will be provided in the Study Pharmacy Manual.
6.6
DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES
Dose modification associated with AL101 is described below in Table 6.
The causality assessment system proposed by the World Health Organization Collaborating 
Centre for International Drug Monitoring, the Uppsala Monitoring Center (WHO-UMC)9 will be 
used by the Investigator for assessing drug-related (certain, probable/likely, possible) 
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 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 allowed only after discussion and approval of the Sponsor’s 
Medical Monitor. Maximum AL101 treatment interruption allowed is 28 days; treatment 
interruption longer than 28 days will result in discontinuation of patient from the study. 
Additional treatment guidelines may be implemented by the Investigators, with agreement of the 
Sponsor/Medical Monitor, as needed to ensure patient safety.
9 “The use of the WHO-UMC system for standardized case causality assessment” a communication by WHO-UMC 
in 2011; https://www.who-umc.org/media/164200/who-umc-causality-assessment_new-logo.pdf 
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Table 6
Dose Modification Criteria for AL101 
AL101 modification 
Note: for any questions, please contact the Sponsor’s Medical Monitor.
Dose Modification Criteria for 
AL101 -Related Adverse 
Events
Cohort 1 (4 mg QW IV)
Cohort 2 (6 mg QW IV)
Grade 4 neutropenia lasting ≥ 7 
days 
Decrease by 1 dose level to 2.4 mg QW.
Decrease dose to 4 mg QW for first episode and to 
2.4 mg QW for second episode
Grade 3 febrile neutropenia 
lasting > 24 hours 
Decrease by 1 dose level to 2.4 mg QW.
Decrease dose to 4 mg f QW or first episode and to 
2.4 mg QW for second episode.
Grade 4 febrile neutropenia 
Discontinue.
Discontinue.
Grade 4 thrombocytopenia or 
≥ Grade 3 thrombocytopenia 
with significant bleeding 
Decrease by 1 dose level to 2,4 ng QW.
Decrease dose to 4 mg QW for first episode and to 
2.4 mg QW for second episode
≥ Grade 3 CD4+ T-cell depletion 
(counts < 200 cells/μL)
Interrupt AL101 until resolution to Grade 1, then 
resume at 1 dose level lower (i.e., 2.4 mg QW) .
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
Interrupt AL101 until resolution to Grade 1, then resume 
at 4 mg QW dose level. For second episode, reduce dose 
to 2.4 mg QW.
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
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. Patients 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 patients that cannot tolerate loperamide 
or do not get adequate relief with maximum 
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. Patients 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 patients that cannot tolerate loperamide or do 
not get adequate relief with maximum doses, 
standard doses of LOMOTIL® 
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AL101 modification 
Note: for any questions, please contact the Sponsor’s Medical Monitor.
Dose Modification Criteria for 
AL101 -Related Adverse 
Events
Cohort 1 (4 mg QW IV)
Cohort 2 (6 mg QW IV)
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.
(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:

Evaluate patient 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. Patients 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 patients 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 patient 
has progressed to Grade 2, or after Grade 1 with no 
Guidelines for the management of diarrhea:

Evaluate patient 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. Patients 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 patients 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 patient has 
progressed to Grade 2, or after Grade 1 with no 
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AL101 modification 
Note: for any questions, please contact the Sponsor’s Medical Monitor.
Dose Modification Criteria for 
AL101 -Related Adverse 
Events
Cohort 1 (4 mg QW IV)
Cohort 2 (6 mg QW IV)
improvement within 3 days with maximum doses of 
loperamide:

Patient 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 patient may continue with 
the dexamethasone or consider switching to 
budesonide 9 mg once daily (QD). Refer to 
Section 7.1.2 for additional instructions on 
premedication with steroids.
Dose modifications for AL101:
Interrupt AL101 until resolution to ≤ Grade 1 (refer 
to Section 7.1.2 for management guidelines for 
diarrhea 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 patient will be discontinued from AL101 
(refer to Section 4.5 for early withdrawal of patients 
from therapy or assessment).
If treatment interruption is longer than 28 days, the 
patient will be discontinued from AL101 (refer to 
Section 4.5 for early withdrawal of patients from 
therapy or assessment).
improvement within 3 days with maximum doses of 
loperamide:

Patient may be treated with dexamethasone at a 
dose of 8 mg Q8h for up to 5 days.  If still no 
improvement in symptoms, the patient may 
continue with the dexamethasone or consider 
switching to budesonide 9 mg QD. Refer to 
Section 7.1.2 for additional instructions on 
premedication with steroids.
Dose modifications for AL101:
Interrupt AL101 until resolution to ≤ Grade 1 (refer to 
Section 7.1.2 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 patient will be discontinued from AL101 (refer to 
Section 4.5 for early withdrawal of patients from therapy 
or assessment).
If treatment interruption is longer than 28 days, the 
patient will be discontinued from AL101 (refer to Section 
4.5 for early withdrawal of patients from therapy or 
assessment).
Grade 3 diarrhea
Guidelines for the management of diarrhea:
Guidelines for the management of diarrhea:
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AL101 modification 
Note: for any questions, please contact the Sponsor’s Medical Monitor.
Dose Modification Criteria for 
AL101 -Related Adverse 
Events
Cohort 1 (4 mg QW IV)
Cohort 2 (6 mg QW IV)

Evaluate patient 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. Patients 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 patients 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 patient 
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 patient may 
continue with the dexamethasone or 
consider switching to budesonide 9 mg QD. 
Refer to Section 7.1.2 for additional 
instructions on premedication with steroids.
Dose modifications for AL101:

Evaluate patient 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. Patients 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 patients 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 patient 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 patient may continue with the 
dexamethasone or consider switching to 
budesonide 9 mg QD. Refer to Section 7.1.2 for 
additional instructions on premedication with 
steroids.
Dose modifications for AL101:
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AL101 modification 
Note: for any questions, please contact the Sponsor’s Medical Monitor.
Dose Modification Criteria for 
AL101 -Related Adverse 
Events
Cohort 1 (4 mg QW IV)
Cohort 2 (6 mg QW IV)
Interrupt AL101 until resolution to ≤ Grade 1 (refer 
to Section 6.6.2 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 patient will be discontinued from AL101 
(refer to Section 4.5 for early withdrawal of patients 
from therapy or assessment).
If treatment interruption is longer than 28 days, the 
patient will be discontinued from AL101 (refer to 
Section4.5 for early withdrawal of patients from 
therapy or assessment).
Interrupt AL101 until resolution to ≤ Grade 1 (refer to 
Section 7.1.2 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 patient will be discontinued from AL101 (refer to 
Section 4.5 for early withdrawal of patients from therapy 
or assessment).
If treatment interruption is longer than 28 days, the 
patient will be discontinued from AL101 (refer to Section 
4.5 for early withdrawal of patients from therapy or 
assessment).
Grade 4 diarrhea
Guidelines for the management of diarrhea:

Evaluate patient 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. Patients 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.
Guidelines for the management of diarrhea:

Evaluate patient 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. Patients 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 patients that cannot tolerate loperamide or do 
not get adequate relief with maximum doses, 
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AL101 modification 
Note: for any questions, please contact the Sponsor’s Medical Monitor.
Dose Modification Criteria for 
AL101 -Related Adverse 
Events
Cohort 1 (4 mg QW IV)
Cohort 2 (6 mg QW IV)

For patients 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 patient may 
continue with the dexamethasone or 
consider switching to budesonide 9 mg QD. 
Refer to Section 7.1.2 for additional 
instructions on premedication with steroids. 
If the above measures have not worked, or patient 
has progressed to Grade 4, consult GI as necessary 
to evaluate for colitis.
Dose modifications for AL101:
Permanently discontinue AL101 (refer to Section 
4.5 for early withdrawal of patients from therapy or 
assessment).
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 patient may continue with the 
dexamethasone or consider switching to 
budesonide 9 mg QD. Refer to Section 7.1.2 for 
additional instructions on premedication with 
steroids.
If the above measures have not worked, or patient has 
progressed to Grade 4, consult GI as necessary to 
evaluate for colitis.
Dose modifications for AL101:
Permanently discontinue AL101 (refer to Section 4.5 for 
early withdrawal of patients from therapy or assessment).
Diagnosed or suspected clinically 
significant gastrointestinal (GI) 
bleeding or unexplained drop in 
hemoglobin
Interrupt AL101, perform appropriate diagnosis and 
treatment.
If GI bleeding is considered related to AL101 reduce 
1 dose level to 2.4 mg QW.
Interrupt AL101, perform appropriate diagnosis and 
treatment.
If GI bleeding is considered related to AL101, Decrease 
to 4 mg QW for first episode and to 2.4 mg QW for 
second episode 1 dose level.
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AL101 modification 
Note: for any questions, please contact the Sponsor’s Medical Monitor.
Dose Modification Criteria for 
AL101 -Related Adverse 
Events
Cohort 1 (4 mg QW IV)
Cohort 2 (6 mg QW IV)
If colitis is suspected please refer to Section 8.4.2, 
Table 10 for management guidelines for colitis.
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
If colitis is suspected please refer to Section 8.4.2, 
Table 10  for management guidelines for colitis.
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
Grade 3 or 4 gastric hemorrhage
Permanently discontinue AL101 (refer to Section 
4.5 for early withdrawal of patients from therapy or 
assessment).
Permanently discontinue AL101 (refer to Section 4.5 for 
early withdrawal of patients from therapy or assessment).
QTcF > 500 msec confirmed by 
at least one repeat ECG and at 
least 50 msec above baseline 
Interrupt if needed to optimize electrolyte 
management. If persists after electrolyte 
optimization (including dose modification of AL101 
if necessary), discontinue.
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
Interrupt if needed to optimize electrolyte management. 
If persists after electrolyte optimization (including dose 
modification of AL101 if necessary), discontinue.
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
AST or ALT > 5 times the 
institutional ULN 
Interrupt AL101 until resolution to ≤ Grade 1 and 
then resume at 1 dose level lower (i.e., 2.4 mg QW).
Refer to Section 8.4.1 for hepatic function 
abnormalities and Section 8.4.5 for drug-induced 
liver toxicity management.
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
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.
Refer to Section 8.4.1 for hepatic function abnormalities 
and Section 8.4.5 for drug-induced liver toxicity 
management.
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
Hy’s law cases (e.g. drug induced 
liver injury; DILI) as defined in 
Section 8.4.1 and assessed by the 
Investigator and Sponsor
Immediately discontinue (refer to Section 4.5 for 
early withdrawal of patients from therapy or 
assessment).
Immediately discontinue (refer to Section 4.5 for early 
withdrawal of patients from therapy or assessment).
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AL101 modification 
Note: for any questions, please contact the Sponsor’s Medical Monitor.
Dose Modification Criteria for 
AL101 -Related Adverse 
Events
Cohort 1 (4 mg QW IV)
Cohort 2 (6 mg QW IV)
Triglyceride Grade 3 elevations 
that persist after 4 weeks of 
medical management
Interrupt AL101 until resolution to ≤ Grade 1 and 
then resume at 1 dose level lower (i.e., 2.4 mg QW).
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
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 
patient will be discontinued from the study.
Grade 2 infusion-related reaction 
Before next dose, premedicate with H1- and 
H2-blockers (diphenhydramine and ranitidine or 
equivalents) or dexamethasone (Refer to 
Section 7.1.2 for additional instructions on 
premedication with steroids).
Refer to Section 6.6.1 for management of infusion-
related reaction.
Before next dose, premedicate with H1- and H2-blockers 
(diphenhydramine and ranitidine or equivalents) or 
dexamethasone (Refer to Section 7.1.2 for additional 
instructions on premedication with steroids).
Refer to Section 6.6.1 for management of infusion-
related reaction.
≥ Grade 3infusion-related 
reaction
Interrupt AL101 (refer to Section 6.6.1 for 
management of infusion-related reaction).
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
Interrupt AL101 (refer to Section 6.6.1 for management 
of infusion-related reaction).
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study.
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 resume at 1 dose level lower (i.e., 2.4 mg QW).
If treatment interruption is longer than 28 days, the 
patient will be discontinued from the study (refer to 
Section 4.5 for early withdrawal of patients from 
therapy or assessment).
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 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 
patient will be discontinued from the study (refer to 
Section 4.5 for early withdrawal of patients from therapy 
or assessment).
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AL101 modification 
Note: for any questions, please contact the Sponsor’s Medical Monitor.
Dose Modification Criteria for 
AL101 -Related Adverse 
Events
Cohort 1 (4 mg QW IV)
Cohort 2 (6 mg QW IV)
Grade 4 non-hematologic AEs 
including Grade 4 non-
hematologic lab abnormalities 
lasting > 72 hours
Permanently discontinue from IP (refer to Section 
4.5 for early withdrawal of patients from therapy or 
assessment).
Permanently discontinue from IP (refer to Section 4.5 for 
early withdrawal of patients from therapy or assessment).
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6.6.1
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)10; 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, premedication with H1- and H2-blockers 
(diphenhydramine and ranitidine or equivalents) or dexamethasone (Refer to Section 7.1.2 for 
additional instructions on premedication with steroids) will be given.
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 patient,

Administer IV antihistamines (diphenhydramine 25 to 50 mg), and ranitidine,

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 many 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 and disconnect infusion tubing from patient,

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 (see Section 8.2),

Also report to Sponsor as an AESI
10 Taxol (paclitaxel) label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf 
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Other symptoms associated with hypersensitivity reactions include facial flushing, chest pain 
and tightness, back pain and GI symptoms, leg pain and cough.
A suggested approach for retreatment after a Grade 3 or greater hypersensitivity reaction 
despite premedication as above is indicated in Section Error! Reference source not found.. 
Such cases should be discussed between the Sponsor/Medical Monitor and Investigator prior to 
retreatment.
6.6.2
Guidelines for Management of Diarrhea
The following are guidelines for the management of diarrhea 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. 
Patients 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. Patients 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 patients not taking the maximum doses, and these cases have 
improved after loperamide was taken more frequently. For patients who 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. Interrupt AL101 dosing
For Grade 2 or higher 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 dexamethasone co-administration should be considered.
3. 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, patients should be instructed to increase fluid 
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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.
4. Treat with dexamethasone
For Grade 2 or higher diarrhea that is not adequately controlled with loperamide and dose 
interruption, administration of dexamethasone may be considered at the discretion of the 
treating physician/investigator. In nonclinical models of other GSIs, coadministration of 
dexamethasone has been shown to decrease the severity of intestinal pathology.(Real, 2009; 
Wei, 2010). Dexamethasone may be administered per os (PO) or IV, as appropriate. As there is 
no reported human experience with the use of dexamethasone for this indication, it is not 
known whether this effect will occur in humans at achievable exposures of dexamethasone. In 
a small number of cases, administration of dexamethasone 8 mg to 10 mg daily, followed by 
tapering over several days, may have contributed to the improvement of diarrhea. If, in the 
judgment of the investigator, it is in the patient’s best interest to receive additional treatment 
with AL101 (for example, the patient has a response to therapy), dexamethasone co-
administration with future doses may be used after discussion with the Sponsor/medical 
monitor. In such cases, dexamethasone 8 mg to 10 mg daily for 2 days to 3 days, beginning on 
the day of AL101`dosing followed by tapering over several days, may be appropriate.
For diarrhea associated with signs of colitis (e.g., fever, peritoneal signs, or significant GI 
bleeding), administration of dexamethasone and antibiotics should be considered. Also, 
inpatient hospitalization, bowel rest, and radiological evaluation may be appropriate if there are 
signs of possible intestinal perforation.
7
STUDY RESTRICTIONS
7.1
PRIOR AND CONCOMITANT THERAPY
7.1.1
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.
In order to prevent a hypersensitivity reaction, all patients 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 patients 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 
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discontinuation plan, the patient 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 patient experiences a Grade 3 or 4 infusion-related reaction despite pretreatment with the 
H1- and H2-blockers then the patient, if re-treated, should also be premedicated with 
corticosteroids (as described in Section 7.1.2) in addition to the H1- and H2-blockers). In the 
event that a patient has a repeat Grade 3 or 4 infusion-related reaction despite premedication 
with H1- and H2-blockers and steroid, the patient must not receive any further treatment with 
AL101, unless agreed by the Sponsor/Medical Monitor and investigator that it is in the 
patient’s best interest to continue treatment (e.g. patient 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).
7.1.2
Premedication with Corticosteroids
All patients 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.
7.1.3
Allowed Medications
All treatments that the Investigator considers necessary for a patient’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 investigational 
product and 30 days after the last dose of investigational product should be recorded. 
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Concomitant medications administered after 30 days after the last dose of investigational 
product should be recorded for SAEs and AESIs as defined in Section 8.4. In addition, all prior 
therapies for ACC should be recorded.
Allowed concomitant therapies:

Glucocorticoids may be administered for treatment of infusion reaction and as 
premedication to prevent further infusion reaction (maximum daily dose of prednisone or 
equivalent ≤ 10 mg/day).

In Cohort 2, in case of toxicity (e.g., GI AEs), per discretion of the Investigator and in 
consultation with the Sponsor’s Medical Monitor, dexamethasone (Refer to Section 7.1.2) 
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.

Patients with castration resistant prostate cancer who have not undergone surgical 
orchiectomy can continue on medical therapies (i.e., gonadotropin releasing hormone 
[GnRH] analogs) to maintain castrate levels of serum testosterone. Concurrent treatment 
with ketoconazole or anti-androgens is not permitted, and patients who have discontinued 
these medications must have a washout period of at least 4 weeks or 5 half-lives of the drug 
(whichever is longer) prior to the first dose of investigational product.
7.1.4
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 patient’s primary care physician. However, the decision to continue the patient on study 
therapy or vaccination schedule requires the mutual agreement of the Investigator, the Sponsor 
and the patient.
Patients 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.

Note: the following situations are considered 1 line of therapy:

Discontinuation of one drug in a multi-drug regimen and continuation of (an) other 
drug(s).

Restarting the same regimen after a drug holiday.

Switching from IV to oral formulation of the same drug is also considered one 
regimen.
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
Exposure to any investigational drug within 4 weeks or 5 half-lives whichever is longer or 
concurrently with investigational product 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 investigational product 
administration.

Use of medications causing Torsades de Pointes within 1 week or 5 half-lives (whichever is 
longer; see Appendix A).

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; see 
Appendix B).

At least 6 months must have elapsed after prior therapy with any investigational nucleoside 
analogue.
Patients 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. Patients 
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.
7.2
DIETARY AND OTHER RESTRICTIONS

Grapefruit and Seville oranges and their juices can inhibit CYP3A4 and should not be 
consumed excessively while on study.

Patients 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 patient, if appropriate.

Patients 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 patients.
Refer to the IB for further information (Section 7).
7.3
CONTRACEPTION
Refer to Appendix E for country-specific requirements on contraception language.
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7.3.1
US and Canada 
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 2 methods 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. The two birth 
control methods can be either two barrier methods or a barrier method plus a hormonal method 
to prevent pregnancy. Patients should start using birth control for 30 days prior to treatment 
initiation (Cycle 1, Day 1) and throughout the study period up to 90 days after the last dose of 
investigational product.
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Patients should be informed that taking the investigational product 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 90 days after the last dose of investigational product. 
Reporting of Pregnancy and Lactation to the Sponsor Medical Monitor is required (see Section 
8.6). If there is any question that a patient will not reliably comply with the requirements for 
contraception, that patient should not enter the study.
7.3.2
Europe 
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. 
Patients should start using birth control for 30 days prior to treatment initiation (Cycle 1, Day 
1) and throughout the study period up to 90 or 120 days (Refer to Appendix E).
for country-specific requirements) after the last dose of investigational product.
The following are considered highly effective method of contraception:
For women of childbearing potential, including female study participants and partners of male 
participants, effective contraception is defined as follows:

combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
-
oral
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-
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 patients 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 90 or 120 days (Refer to Appendix E) for country-specific requirements) after the last dose 
of investigational product, unless permanently sterile by bilateral orchidectomy.
Patients should be informed that taking the study drug 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 90 or 120 days (Refer to Appendix E) for country-specific requirements) 
after the last dose of investigational product. Reporting of Pregnancy and Lactation to the 
Sponsor Medical Monitor is required (see Section 8.6). If there is any question that a patient 
will not reliably comply with the requirements for contraception, that patient should not enter 
the study.
7.3.3
Use in Pregnancy
If a patient inadvertently becomes pregnant while on treatment with AL101, the patient will 
immediately be removed from the study. The site will contact the patient at least monthly and 
document the patient’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the Sponsor Medical Monitor (or designee) 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the mother 
or newborn). The study Investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor. If a 
male patient impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor Medical Monitor (or designee) and 
followed as described above.
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7.3.4
Use in Nursing Women
It is unknown whether AL101 is excreted in human milk. Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
patients who are breast-feeding are not eligible for enrollment.
8
SAFETY AND PHARMACOVIGILANCE
The Investigator is responsible for the detection and documentation of events meeting the 
criteria and definition of an AE or SAE as provided in this protocol. Throughout the study, AEs 
will be recorded in the source documents and on the appropriate pages of the eCRF regardless 
of whether the AEs are considered related to active product. To avoid confusion, the AE should 
be recorded in standard medical terminology.
8.1
ADVERSE EVENT
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring 
in any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition. AEs include:

Worsening (change in nature, severity, or frequency) of conditions present at the 
onset of the study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline within the range 
of normal that the Investigator considers to be clinically important), refer to Section 8.1.1.

Clinically significant abnormalities in physical examination, vital signs, and weight
Note that progressive disease should not be reported as an AE.
Table 7 summarizes the reporting requirements for AEs, SAEs, AESI and pregnancy.
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Table 7
Adverse Event Observation Periods
Type of 
Event
Adverse Event
Serious Adverse 
Event
AESI related to 
investigational 
product
Pregnancy
Reporting 
period
From consent 
until 30 days 
after last dose of 
investigational 
product
From consent until 30 
days after the last 
dose of investigational 
product for all SAEs, 
and any time after the 
end of study for SAEs 
believed to be related 
to investigational 
product
From consent until 
30 days after the last 
dose of 
investigational 
product, or the 
initiation of a new 
anti-cancer therapy
From consent until 
90 days after last 
dose of 
investigational 
product
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
AEs occurring from the time of consent until the time of the first dose of investigational 
product which are attributed to study procedures must be reported on the designated AE eCRF. 
All AEs, including AEs attributed to study procedures, occurring from the first dose of 
investigational product until 30 days after last investigational product or until the event has 
resolved, stabilized or an outcome has been reached must be reported on the AE eCRF, 
regardless of the severity or relationship to investigational product. The Investigator should 
treat patients with AEs appropriately and observe them at suitable intervals until the events 
stabilize or resolve. AEs are identified through observation or examination of the patient, 
questioning of the patient, complaint by the patient, or by abnormal clinical laboratory values.
8.1.1
Abnormal Laboratory which Are Considered AEs
In addition, AEs may also include laboratory values that become significantly out of normal 
range. Such abnormal laboratory values or test results constitute AEs if they induce clinical 
signs or symptoms, require investigational product dose modifications or are considered 
clinically significant (e.g., cause study discontinuation or constitutes in and of itself a Serious 
Adverse Event, or require therapy, e.g., any hematologic abnormality that requires transfusion 
or cytokine treatment); and should be recorded on the AE eCRF under the signs, symptoms or 
diagnosis associated with them. In the event of an out-of-range value (abnormal, not clinically 
significant), the laboratory test should be repeated until it returns to normal or can be explained 
and the patient’s safety is not at risk.
8.1.2
Events not considered AEs
The following events/medical conditions are not considered AEs:

Disease progression (unless considered to be drug related by the Investigator).
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
Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that are 
present prior to study entry and do not worsen during the study

Interventions for pretreatment conditions (e.g., elective cosmetic surgery) or medical 
procedures that were planned before study enrollment.

Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion). 
The condition that leads to the procedure is an AE if not present at baseline.

Hospitalization for elective surgery planned prior to study (situation where an untoward 
medical occurrence has not occurred).

Pregnancy will not be considered an AE, but if occurs, will be reported on pregnancy form.
8.1.3
AE Assessments
Severity of the AE will be assessed by the investigating physician in accordance with 
NCI-CTCAE v5.0 (Table 8). The Investigator should only use the term grade in Table 8 to 
describe the intensity of the AE. Only one severity definition should be used for each AE (e.g., 
"mild/moderate" is not acceptable).
Table 8
Definition of Adverse Events Intensity According to NCI-CTCAE v5.0
Intensity 
Grade
Criteria1
Mild 
1
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Moderate 
2
Minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activity of daily living (ADL)2
Severe 
3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL3
Life 
Threatening 
4
Life-threatening consequences; urgent intervention indicated
Death 
5
Death related to adverse event
1 A Semi-colon indicates ‘or’ within the description of the grade.
2 Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
3 Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.
The Investigator will document in his/her opinion the relationship of the AE to the 
investigational product using WHO-UMC criteria outlined in Table 9. If the relationship 
between the AE/SAE and the investigational product is determined to be “possibly related” or 
“probably related” or “definitely related” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting.
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Table 9
WHO-UMC Adverse Events Causality Criteria
Causality term
Assessment Criteria*
Certain 

Event or laboratory test abnormality, with plausible time 
relationship to drug intake

Cannot be explained by disease or other drugs

Response 
to 
withdrawal 
plausible 
(pharmacologically, 
pathologically)

Event definitive pharmacologically or phenomenologically (i.e. 
an objective and specific medical disorder or a recognized 
pharmacological phenomenon)

Rechallenge satisfactory, if necessary 
Probable/ Likely 

Event or laboratory test abnormality, with reasonable time 
relationship to drug intake

Unlikely to be attributed to disease or other drugs

Response to withdrawal clinically reasonable

Rechallenge not required 
Possible 

Event or laboratory test abnormality, with reasonable time 
relationship to drug intake

Could also be explained by disease or other drugs

Information on drug withdrawal may be lacking or unclear 
Unlikely 

Event or laboratory test abnormality, with a time to drug intake 
that makes a relationship improbable (but not impossible)

Disease or other drugs provide plausible explanations 
Conditional/ Unclassified 

Event or laboratory test abnormality

More data for proper assessment needed, or

Additional data under examination 
Unassessable/ 
Unclassifiable 

Report suggesting an adverse reaction

Cannot be judged because information is insufficient or 
contradictory
Data cannot be supplemented or verified 
* All points should be reasonably complied with
Source: https://www.who-umc.org/media/164200/who-umc-causality-assessment_new-logo.pdf
Outcome to Date are classified as follows:

Recovered – The patient has fully recovered from the AE with no residual effects 
observable

Recovered with sequelae – The patient has recovered from the AE with residual effects 
observable

Recovering – The patient status improved but has been recovered
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
Ongoing – AE is not recovered

Fatal

Unknown
AEs will be coded by Data Management using the Medical Dictionary for Regulatory 
Activities (MedDRA) AE dictionary (version to be specified in the statistical analysis plan; 
SAP).
All AEs, serious and not serious, will be recorded on the AE Case Report Form page. Severity 
and relationship to investigational product will be assessed by the Investigator as described in 
the section above.
Follow-up Reports for Non-Serious AEs
All AEs must be followed until resolution or stabilization or are otherwise explained. Non-
related AE without end dates at the end of study visit will be marked ‘ongoing’.
8.2
SERIOUS ADVERSE EVENT (SAE)
A serious AE (SAE) is any AE occurring at any dose that results in any of the following 
outcomes:

Death

Is life-threatening

Requires inpatient hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions

A congenital anomaly or birth defect

Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include Grade 3 or 4 infusion 
reactions, allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization.
Note that hospitalization is defined as admission to treat a clinical adverse event. The following 
events would not be considered hospitalizations for SAE reporting purposes: 23-hour hold for 
observation, admission to a hospice facility or nursing home, respite care, outpatient surgery, 
social admission (e.g., a homeless patient) or admission not associated with a precipitating 
clinical adverse event (e.g., elective or pre-planned surgery, or in-patient administration of 
subsequent chemotherapy, etc.).
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Note: In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same timeframe as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the Sponsor 
for collection purposes.

Is a new cancer (that is not a condition of the study).

Is associated with an overdose.
8.3
UNEXPECTED ADVERSE EVENT
An unexpected AE is any AE, the specificity or severity of which is not consistent with 
information in the clinical protocol or current Investigator’s Brochure for an unapproved 
investigational product or package insert/summary of product characteristics for an approved 
product (package inserts are available separately at the participating center).
Serious Unexpected Suspected Adverse Reaction (SUSAR) is a serious adverse reaction 
assessed as unexpected by the Sponsor and that is judged by either the reporting Investigator or 
the Sponsor to have a reasonable causal relationship to a investigational product.
8.4
ADVERSE EVENTS OF SPECIAL INTEREST
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product 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 investigational product. 
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 
potential drug-induced liver injury (DILI). For dose modifications and toxicity management for 
the AESI, please refer to Section 6.6.
8.4.1
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 section 1.5 of 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. 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 investigational 
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product. Guidelines for management of patients with hepatic function abnormality are outlined 
in Section 8.4.1.
Cases where a patient shows an AST or ALT ≥3ULN or 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. Investigational product should be interrupted immediately if any Hy’s law cases 
(section 8.4.5).
8.4.2
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 10.
Table 10
Colitis Management
Grade
Dose Modification
Management
Any Grade

Patients 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: 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 

Promptly start prednisone 1 to 2 mg/kg/day or IV 
equivalent

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 and prompt treatment with IV 
methylprednisolone 2- 4mg/kg/day started.

Caution: Important to rule out bowel perforation
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Grade
Dose Modification
Management
to 2.4 mg QW for 
third episode.
If on AL101 4 mg 
QW: decrease dose 
to 2.4 mg QW

Consult study physician if no resolution to ≤ Grade 1 
in 3-4 days
Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and anti 
PCP treatment (please refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation])
Grade 3-4
Permanently 
discontinue 
investigational 
product

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
Caution: Ensure GI consult to rule out bowel perforation
Once improving, gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, antifungals and anti 
PCP treatment (please refer to current NCCN guidelines 
for treatment of cancer-related infections [Category 2B 
recommendation])
8.4.3
Infusion Reactions including Anaphylaxis
In study CA216001 1 patient developed Grade 3 anaphylaxis, a dose limiting toxicity (DLT) at 
the 4 mg dose. In case of Grade 3 or 4 allergic reaction, stop investigational product infusion 
and disconnect infusion tubing from the patient.
For infusion reactions, refer to Section 6.6.1.
8.4.4
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 (patient 3-37) was assessed 
as related AL101 and occurred 3-5 months after initiation of AL101.

In the current AL-ACC-01 (ACCURACY) study, a Grade 1 keratoacanthoma (patient 
no. 1101-002), was assessed by both the Investigator and the Sponsor as related to 
AL101 and unexpected
All patients 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 patients will be counseled to avoid excessive sun and UV exposure during 
the study.
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8.4.5
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 Section 8.5 for reporting details). 
The criteria for identifying p-DILI events depend on whether the patient’s baseline liver 
biochemistry is normal or abnormal (see Figure 2).
Figure 2
Algorithm for p-DILI identification and mandatory SAE reporting in 
patients 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 patient 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 
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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 
patient with an abnormal Hepatic Laboratory Panel that meets p-DILI criteria (see Figure 2) is 
a candidate for investigational product 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.
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 patient’s 
age, gender, clinical history, and signs and symptoms.
8.5
NOTIFICATION OF SERIOUS UNEXPECTED SUSPECTED ADVERSE EVENT
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.
For the time period beginning when the consent form is signed until treatment initiation (Cycle 
1, Day 1), any SAE, or follow up to an SAE, including death due to any cause other than 
progression of the cancer under study, that occurs to any patient must be reported within 24 
hours to the Sponsor if it causes the patient 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.
For the time period beginning at treatment initiation (Cycle 1, Day 1) through 30±1 days 
following cessation of investigational product (EOS visit), any SAE, or follow up to an SAE, 
including death due to any cause other than progression of the cancer under study, whether or 
not related to the Sponsor's product, must be reported within 24 hours to the Sponsor.
Additionally, any SAE, considered by an Investigator who is a qualified physician to be related 
to the investigational product that is brought to the attention of the Investigator at any time 
following consent through the end of the specified safety follow-up period (specified above), or 
at any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor.
Initial Notification
Upon identification, all SAEs will be reported by the site within 24 hours using the appropriate 
eCRF. If eCRFs are not available, SAEs should be reported by email to Clinical Safety 
within 24 hours:
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Sponsor’s Medical Monitor(s):
Gilad Gordon
Email: ggordon@orragroup.com 
CRO Safety contact information:
Email: Safety_Ayala-AL-ACC-101@precisionformedicine.com
Fax: 760-683-6433
These preliminary reports will be followed within 24 hours by more detailed descriptions that 
will include a completed SAE form, copies of hospital case reports (i.e., hospital progress 
notes, results of applicable diagnostic tests, laboratory results and biopsy results), autopsy 
reports, and other documents, when requested and applicable.
For regulatory purposes, the initial SAE reports should include:
a)
a suspected investigational product
b) 
an identifiable patient (e.g., study patient code number)
c) 
an AE with a seriousness and the Investigator’s assessment of the relationship to 
investigational product
d) 
an identifiable reporting source (Investigator contact details)
Once reported, the SAE form and accompanying documentation should be placed in the SAE 
section of the Investigator’s site file.
In addition, all AEs / SAEs / SUSARs will be reported to the IRB/IEC and regulatory 
authorities as required by local regulations and ICH-GCP guidelines.
Follow-up of SAEs / SUSARs
Follow-up of SAEs / SUSARs that occur during the study will continue until their satisfactory 
resolution or stabilization. In outstanding cases, it may be defined as “ongoing without further 
follow-up” by the Investigator and Sponsor’s decision.
When supplementary information is available, a follow-up SAE Report Form must be 
completed by the site (marked as “follow-up report”). The contact report information for 
follow-up SAE reporting is the same as for initial SAE reports (see above section).
Accompanying documentation, such as copies of hospital case reports, autopsy report, and 
other documents when applicable, should be sent as soon as they are available.
Once reported, the SAE form and accompanying documentation should be placed in the SAE 
section of the Investigator’s site file. If supplementary information on a SAE has to be sent, the 
SAE form has to be used marked as “follow-up report”.
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Patients who have had an SAE during the treatment period must be followed clinically until all 
parameters (including laboratory) have either returned to normal or have stabilized or are 
otherwise explained.
Any newly emergent SAEs after treatment is discontinued or the patient has completed the 
study and is considered to be related to the investigational product or study participation should 
be recorded and reported immediately. The post-study period for the purpose of SAE reporting 
is up to 90 days following last visit of the study.
8.6
PREGNANCY
If a patient inadvertently becomes pregnant while on investigational product, the patient will 
immediately be removed from the study (see Section 7.3 on contraception). Full details will be 
recorded on the withdrawal page of the eCRF. Although pregnancy and lactation are not 
considered AEs, it is the responsibility of Investigators or their designees to report any 
pregnancy or lactation in a patient (spontaneously reported to them) that occurs during the 
study.
Pregnancies and lactations that occur after the ICF is signed but before treatment initiation 
(Cycle 1, Day 1) must be reported by the Investigator if they cause the patient to be excluded 
from the study or are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
Pregnancies and lactations that occur from the time of treatment initiation (Cycle 1, Day 1) 
through 90 days following cessation of Sponsor’s investigational product, or 30 days following 
cessation of investigational product if the patient initiates new anticancer therapy, whichever is 
earlier, must be reported by the Investigator within the same timelines as an SAE (within 24 
hours) on a Pregnancy Monitoring Form. All reported pregnancies must be followed to the 
completion/termination of the pregnancy. If the outcome is an SAE (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn) before end of study, the Sponsor must be notified within 24 hours using an SAE 
Report Form. If the pregnancy continues to term, the outcome (health of infant) must also be 
reported.
If a male patient impregnates his female partner, the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and followed as described 
above.
All supporting source documentation including but not limited to: any hospital admission or 
discharge reports, SAE report (updated or original), clinic chart documents etc. should be kept 
in the patient record.
8.7
OVERDOSE
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 8.4.5 for reporting details).
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9
STATISTICAL ANALYSIS PLAN
9.1
GENERAL
This is a Phase 2, multicenter, single-agent, open-label study. Since this is an open-label, 
clinical study, descriptive summary statistics will be employed to analyze the data.
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. 
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 investigational product 
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).
9.2
SAMPLE SIZE CONSIDERATION
The study was initiated as a Simon’s two-stage optimal design.
The study passed the futility analysis in Stage 1 of the Simon two-stage design and is currently 
continuing to enroll patients. While the data on Cohort 1 (4 mg QW) is maturing, the study will 
enroll up to a maximum of 45 patients in Cohort 1 and in parallel will be expanded with the 
addition of Cohort 2 (6 mg QW). The study will continue enrolling a total of 42 patients in 
Cohort 2, 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 patient. A second look is 
may be undertaken at 50% of the total information fraction (21 patients) for Cohort 2.
The updated design, a 2-look Group Sequential design with stopping for futility based on 
Pocock beta-spending function takes the first look after 21 patients and has the following 
operating characteristics:
Total n
Stages
1st look n
2nd look n
r1 futility
r2 futility
Power
42
2
21
42
2
6
89.4
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The expansion of Cohort 1 to a maximum of 45 patients and Cohort 2 to a maximum of 42 
patients will provide at least 80% power to test the hypothesis of achieving an increase of the 
response rate from 8% to 25% using a type I error of 5%.
9.3
ANALYSIS SETS
The following analysis sets will be used in this study:

Safety analysis set: All patients who receive at least one dose of investigational product 
(even a partial dose).

Efficacy evaluable set: All patients who receive at least one dose of investigational product, 
have measurable disease at baseline per RECIST v1.1 or modified MDA criteria for bone-
exclusive disease (see Table 11), and have at least one post-baseline on-study assessment 
of tumor response.

Per-protocol (PP) analysis set: All efficacy evaluable patients who have no major protocol 
violations, as defined by the Sponsor prior to database lock.

PK analysis set includes all patients who receive investigational product and have at least 
one post baseline evaluable PK sample.
9.4
PATIENT DISPOSITION
The number and percentage of patients who are enrolled, treated, discontinued from 
investigational product, and participating in follow-up will be presented for the Safety analysis 
set and the Efficacy Evaluable set. A summary of reasons for discontinuation from treatment 
and withdrawal from the study will be provided. The number of patients included in each 
analysis set will be summarized and the reasons for excluding patients from each set will be 
listed.
9.5
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Demographic characteristics including age, gender, race, and ethnicity will be presented in the 
form of tabular summary statistics for all ITT patients. Other patient baseline characteristics 
including weight, height, body mass index (BMI), initial stage of disease, and performance 
status will be presented similarly.
9.6
EFFICACY
9.6.1
Definition of Efficacy Endpoints
The primary efficacy endpoint is the objective response rate (ORR). ORR is defined as the 
proportion of patients who have a best overall response (BOR) of CR or PR as determined 
using RECIST v1.1 or modified MDA criteria for bone-exclusive disease (see Table 11). BOR 
is defined as the best response recorded between the date of first dose of investigational 
product and the date of subsequent anti-cancer therapy. A BOR of CR or PR requires 
confirmation of the assessment at least 4 weeks later.
Other efficacy endpoints are as follows:
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
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.

PFS, defined as the interval from the start of investigational product to the earlier of the 
first documentation of disease progression 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. Patients 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 patient was last known alive, or the data 
cut-off date, whichever is earlier.
9.6.2
Efficacy Analysis
Primary efficacy analysis will be performed on the Efficacy Evaluable set.
The ORR will be estimated based on the proportion of patients with an overall response of 
either CR or PR, taking into account any requirement for confirmation. Disease response will 
be assessed using RECIST v1.1 or modified MDA criteria for bone-exclusive disease (see 
Table 11). The estimate of the ORR will be accompanied by a 2-sided 95% exact binomial 
confidence interval (CI) derived using the Clopper-Pearson method.
DOR, PFS, and OS will be summarized descriptively. The censoring rules will be defined in 
the SAP.
Refer to the SAP for more details.
9.7
SAFETY AND TOLERABILITY ANALYSIS
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 in the Safety analysis set.
Adverse events: The AE verbatim descriptions (investigator terms from the CRF) 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 investigational product until 30 days after the last dose of investigational 
product. The incidence of treatment-emergent AEs will be summarized overall, by system 
organ class and preferred terms, and by severity grade and relationship to investigational 
product. SAEs and AEs leading to discontinuation will also be tabulated.
Other safety data: These data will be summarized by presenting the proportions of patients 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 patients with baseline and at least 1 post baseline assessment. Laboratory data 
will be listed, and abnormal results will be flagged.
9.8
INTERIM ANALYSIS
No formal interim analysis is planned.
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10
DATA MANAGEMENT
10.1
DATA HANDLING AND RECORD KEEPING
Any changes to information in the study progress notes and other source documents will be 
initialed and dated on the day the change is made by a clinical site staff member authorized to 
make the change. Changes will be made by striking a single line through erroneous data and 
clearly entering the correct data (e.g., wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be written adjacent to the change by the 
clinician.
Patient information will be captured and managed by study sites on eCRFs by a web-based 
electronic data capture (EDC) tool developed and supported by CRO and approved by the 
Sponsor. Data should be entered into the EDC system in a timely manner as outlined within the 
eCRF Completion Guidelines. Study sites will enter data directly into an EDC system by 
completing the eCRF via a secure internet connection. Data entered into the eCRF must be 
verifiable against source documents at the study center. Data to be recorded directly on the 
eCRF will be identified and the eCRF will be considered the source document. Any changes to 
the data entered into the EDC system will be recorded in the audit trail and will be Food and 
Drug Administration (FDA) CFR 21 Part 11 compliant. Medical coding will use MedDRA for 
concomitant diseases (Medical History) and AEs and WHO Drug Dictionary for medications.
Missing or inconsistent data will be queried within the EDC system in writing to the 
Investigator for clarification. Subsequent modifications to the database will be documented.
 Data management will be performed by CRO according to their Standard Operating 
Procedures (SOPs). This will include setting up a relevant database and data transfer 
mechanisms, along with appropriate validation of data and resolution of queries. Data 
generated within this clinical study will be handled according to the relevant standard operating 
procedures (SOPs) of the data management and biostatistics departments of the CRO.
10.2
QUALITY CONTROL AND QUALITY ASSURANCE
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Data anomalies will be communicated to 
the sites for clarification and resolution, as appropriate.
During and/or after completion of the study, quality assurance officers assigned by the Sponsor 
or the regulatory authorities may wish to perform onsite audits or inspections. The Investigator 
will be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested.
11
ADMINISTRATIVE ASPECTS
11.1
ETHICAL ASPECTS
The Sponsor, 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 
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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.
11.1.1
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 patients, 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.
11.1.2
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 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.
11.1.3
Patient Information and Informed Consent
It is the responsibility of the Investigator to obtain written informed consent from each patient 
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 patient that he/she is completely free to refuse to 
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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 patient 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. Patients will be informed that their race and ethnicity will be 
collected and will be used during analysis of study results.
The patient also agrees to allow the monitor/auditor/health authorities to verify the collected 
patient data against the patient's original medical records for the purpose of source data 
verification.
The ICF – personally signed and dated by the patient and the Investigator – must be kept in the 
Investigator’s study file by the Investigator(s) and documented in the eCRF and the patient’s 
medical records. The Investigator confirms to the Sponsor to obtain the written informed 
consent from any patient before participating in the study.
If new information becomes available that may be relevant to the patient’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 
patients (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 patients’ participation in the clinical study, this 
should be mentioned in the consent form.
11.1.4
Data and Safety Monitoring
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 patients have been treated for at least 
2 cycles (after the first on-treatment radiographic assessment). Further details are specified in 
the DMC charter. Efficacy data will also be provided to the DMC to allow assessment of 
benefit/risk for patients. 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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11.1.5
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 patient’s right to protection against invasion of 
privacy. Throughout this study, all patient data will be identified only by a patient 
identification number. The personal data will be blinded in all data analyses. The patient 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 patient'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 patient participation in the study.
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 patients’ original medical records for 
verification of clinical study procedures and/or data, without violating the confidentiality of the 
patients to the extent permitted by the law and regulations. In any presentations of the results of 
this study or in publications, the patients’ 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.
11.2
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.
11.3
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 
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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 patient 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 CRFs to be available during a portion of the 
monitoring visit to answer questions, and to provide any missing information.
11.4
STUDY DOCUMENTATION
Study documents will include but not be limited to the following:

Signed ICFs

Source documents (e.g., patient files, medical notes, study worksheets)

Investigator copies of the eCRFs and SAE reports

Investigator site file and contents

Study Manuals (including, but not limited to, Laboratory Manual, Study 
Pharmacy Manual and Imaging Manual)

Investigator meeting binder and or other training materials
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.
11.4.1
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 patient 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 patient 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 patient. In this case, the appropriate regulatory authorities will 
be notified subsequent to the modification.
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11.4.2
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.
11.4.3
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 patients 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.
11.4.4
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 patient’s medical record. Alternatively, the site may create and use their own 
study worksheets. Only a patient identification number will be used to identify the patient. The 
Investigator must keep a separate log of patient 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 patient 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 
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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.
11.4.5
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.
11.4.6
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.
11.5
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.
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.
11.6
STUDY COMPLETION
This study is expected to end when all required patients have been enrolled and the last patient 
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.
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11.7
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.
11.8
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.
11.9
RECORDS
Data collected at Screening and during the study will be recorded in the patient’s source 
documents and retained at the study site for all patients who sign informed consent. Patients 
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, patients will be 
identified only by screening and patient 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.
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.
11.10
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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12
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Xiao, Y. F., Yong, X., Tang, B., Qin, Y., Zhang, J. W., Zhang, D., et al. (2016). "Notch and Wnt 
signaling pathway in cancer: Crucial role and potential therapeutic targets (Review)." 
International journal of oncology 48(2): 437-449.
Zhao, Y. Y., Yu, G. T., Xiao, T. and Hu, J. (2017). "The Notch signaling pathway in head and 
neck squamous cell carcinoma: A meta-analysis." Advances in clinical and experimental 
medicine : official organ Wroclaw Medical University 26(5): 881-887.
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13
APPENDICES
APPENDIX A
DRUGS WITH RISK OF TORSADES 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
Patients are prohibited from taking medications listed in Category 1: Drugs with Risk of 
Torsades de Pointes. Caution is warranted when administering AL101 to patients 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
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APPENDIX B
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 
(http://www.medicine.iupui.edu/clinpharm/ddis/table.asp ). 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 patients
are on treatment with AL101. Some examples of strong inhibitors of CYP3A4 are:
clarithromycin 
nelfinavir
indinavir 
posaconazole
itraconazole 
ritonavir
ketoconazole 
saquinavir
nefazodone 
telithromycin
voriconazole
In addition, excessive consumption of the following foods should be avoided:
Grapefruit and grapefruit juice
Seville oranges and Seville orange juice
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 patients are on
treatment with AL101. Some examples of strong inducers of CYP3A4 are:
avasimine 
phenytoin
carbamazepine 
rifampin
St. John’s wort
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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APPENDIX C
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.
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Evaluation of Tumor Burden at Subsequent Assessments:
Please refer to the SoA (Table 1) for the timing of subsequent imaging assessments.
Target Lesions:
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.
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-
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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 patient’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. 
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 
Bone metastases:
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Evaluation of response in patients with bone-only disease will be performed by MRI (preferred 
modality) per modified MDA criteria (Table 11). CT scans should only be performed when MRI 
is contraindicated (cases of bypass for example).
Table 11
Modified MD Anderson (MDA) Criteria for Bone Metastases+
Response 
Category
Criteria
Normalization of Signal intensity on MRI
Complete 
Response
Complete sclerotic fill-in of lytic lesions or normalization of bone density on CT*
Osteoblastic flare – Interval visualization of lesions with sclerotic rims or new 
sclerotic lesions in the setting of other signs of PR and absence of progressive bony 
disease
≥50% decrease in measurable lesions on MRI 
Partial 
Response
≥50% decrease in measurable lesions or ≥50% subjective decrease on ill-defined 
lesions on CT*
≥25% increase in size of measurable lesions on MRI
≥25% increase in size of measurable lesions or subjective increase in the size of 
ill-defined lesions on CT*
Progressive 
disease
New bone metastasis
No change
<25% increase or <50% decrease in size of measurable lesions
<25% subjective increase or <50% subjective decrease in size of ill-defined lesions
Stable 
disease
No new bone metastasis
*CT only to be performed if MRI is contraindicated
+Measurements are based on the sum of a perpendicular, bidimensional measurement of the greatest diameters of 
each individual lesion
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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APPENDIX D
QUALITY OF LIFE - EORTC QLQ-C30
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APPENDIX E
COUNTRY-SPECIFIC REQUIREMENTS
US and Canada
Section 4.1
Inclusion no. 9:  WOCBP must agree to follow instructions for method(s) of contraception for 
the duration of the treatment with AL101 plus 90 days post-treatment completion.
Inclusion no. 10: Men who are sexually active with WOCBP must agree to follow instructions 
for method(s) of contraception for the duration of treatment with AL101 plus 90 days (duration 
of sperm turnover) post-treatment completion.
Section 7.3:
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 2 methods 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. The two birth control methods can 
be either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
Patients should start using birth control for 30 days prior to treatment initiation (Cycle 1, Day 1) 
and throughout the study period up to 90 days after the last dose of investigational product.
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Patients should be informed that taking the investigational product 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 90 days after the last dose of investigational product. Reporting of 
Pregnancy and Lactation to the Sponsor Medical Monitor is required (see Section 8.6). If there is 
any question that a patient will not reliably comply with the requirements for contraception, that 
patient should not enter the study.
United Kingdom
The following sections were modified per MHRA request and are to be followed in the UK.
1.MHRA requested clarification that CE-marked device for NGS screening will be utilized.
Section 5.4
Notch mutational status from prior tests with any commercially available CE-marked device for 
NGS assay kit will be confirmed centrally.
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2. MHRA requested clarification on contraceptive language for male and female patients.
Section 4.1
Inclusion no. 9: WOCBP must agree to use a highly effective birth control during the study 
(prior to the first dose with AL101 and for 90 days after the last dose), if conception is possible 
during this interval. Female patients 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.
Inclusion no. 10: Male patients with partners who are WOCBP should use a combination of the 
methods specified in Section 7.4 for the women along with a male condom during the study and 
for 90 days after the last dose of investigational product, unless permanently sterile by bilateral 
orchidectomy.
Section 7.3:
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. Patients should 
start using birth control for 30 days prior to treatment initiation (Cycle 1, Day 1) and throughout 
the study period up to 90 days after the last dose of investigational product.
The following are considered highly effective method of contraception:
For women of childbearing potential, including female study participants and partners of male 
participants, 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
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
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 patients 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 90 days after the last dose of investigational product, unless permanently sterile by bilateral 
orchidectomy.
Patients should be informed that taking the investigational product 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 90 days after the last dose of investigational product. Reporting of 
Pregnancy and Lactation to the Sponsor Medical Monitor is required (see Section 8.6). If there is 
any question that a patient will not reliably comply with the requirements for contraception, that 
patient should not enter the study.
France
ANSM require that contraception will be used for 120 days (4 months) post last dose of AL101, 
therefore the following sections were modified and are to be followed in France:
Section 4.1
Inclusion no. 9: WOCBP must agree to follow instructions for method(s) of contraception for the 
duration of the treatment with AL101 and for 120 days (4 months) after the last dose of AL101.
Inclusion no. 10: Men who are sexually active with WOCBP must agree to follow instructions 
for method(s) of contraception for the duration of treatment with AL101 and for 120 days 
(4 months) after last dose of AL101
Section 7.3:
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 2 methods 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. The two birth control methods can 
be either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
Patients should start using birth control for 30 days prior to treatment initiation (Cycle 1, Day 1) 
and throughout the study period up to 120 days (4 months) after the last dose of investigational 
product.
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The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Patients should be informed that taking the investigational product 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 (4 months) after the last dose of investigational product. 
Reporting of Pregnancy and Lactation to the Sponsor Medical Monitor is required (see 
Section 8.6). If there is any question that a patient will not reliably comply with the requirements 
for contraception, that patient should not enter the study.
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APPENDIX F
PROTOCOL AMENDMENT HISTORY AND SUMMARY OF 
CHANGES
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly above the synopsis. Histories for previous global amendments appear below.
The following changes were made to the protocol in reverse chronological order, including country-
specific amendments. Order of changes is presented by order of appearance in the protocol.
AMENDMENT 2 (V3.0); 20 DECEMBER 2019
Protocol Version 
& date
Rev.
Summary of Change
Rationale for Change
Synopsis and Section 2 Objectives and 
Endpoints
Change primary endpoint to be 
Investigator assessed.
Add objective/endpoint for patient 
reported outcome measure (EORTC 
QLQ-C30) to Cohort 2
Investigator-assessed is 
appropriate for this study phase.
Radiological images are being 
collected for central review 
should this become required.
To evaluate the effect of AL101 
6 mg QW on patients’ quality of 
life.
Synopsis and Section 3 Study Design
Add sequential Cohort 2 (6 mg once 
weekly; QW) and clarify enrollment 
process.
Study expansion and higher 
dose (while adhering to set 
safety toxicity management 
guidelines), may improve 
efficacy and maintain patient’s 
safety.
The current results in patients 
with ACC suggest that a higher 
dose of AL101 may be well 
tolerated in this patient 
population particularly with the 
use of steroids and other toxicity 
management guidelines. Prior 
studies suggest that the increase 
to 6 mg will result in a higher 
exposure and more substantial 
inhibition of the Notch pathway 
and this may result in improved 
efficacy in this difficult to treat 
patient population.
Protocol V3.0, 
Amendment 2, 
Global
5.0
Clarify information to be collected for 
medical history.
Collection of scans for 12 
months prior to enrollment are 
intended to allow the 
comparison of the rate of 
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Protocol Version 
& date
Rev.
Summary of Change
Rationale for Change
progression prior and while 
being treated with AL101.
Clarify that enrollment of patients with 
bone exclusive disease will be eligible 
after discussion and approval by the  
Sponsor’s Medical Monitor (patient 
must have evaluable and measurable 
lesions)
Patients with bone disease may 
have lesions that are very 
difficult to measure. Discussions 
with the Sponsor will clarify 
whether the lesions are 
measurable and whether the 
patients qualify for the study.
Clarify that patients with radiological 
progression may continue on 
investigational product provided they 
derive clinical benefits, they consent, 
and this is agreed upon the Investigator 
and Sponsor’s Medical Monitor. 
To allow patients with 
radiological progression who 
derive clinical benefit to 
continue treatment with 
investigational product
Clarify that on-treatment radiological 
scans will be collected and held for 
future retrospective analysis by an 
independent central review.
Retrospective central review is 
appropriate for this study phase.
Synopsis, Section 4.1 Inclusion criteria 
and Section 7.4
Align with study design, and country-
specific requirements; sections refer to 
Appendix E for country-specific 
requirements.
Appendix E (country specific 
requirements) was added to 
address changes to contraceptive 
language requests from MHRA 
and ANSM regulatory agencies.
Synopsis and Section 6.1 
Investigational Product Administration
Add 6 mg QW regimen.
Clarify premedication use for 
medications containing Cremophor.
Align with study design regarding 
continuation of investigational product.
To reflect changes in study 
design.
Premedication is a safety 
precaution to avoid 
hypersensitivity reaction.
Protocol consistency.
Synopsis and Section 9 Statistical 
Analysis
Update sample size consideration.
Revise PK analysis set definition.
Sample size updated to reflect 
changes in study design.
PK is collected for all patients, 
therefore analysis set definition 
was updated.
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Protocol Version 
& date
Rev.
Summary of Change
Rationale for Change
Section 1.3.2 Clinical studies
Update with preliminary data from the 
ongoing ACCURACY study.
To ensure most up-to-date 
information is provided.
Section 1.4. Study Rationale
Update section to reflect change in study 
design.
For consistency throughout the 
protocol.
Section 1.4.1 Dose Selection
Revise to include 6 mg QW dose.
To justify opening Cohort 2.
Section 5.1.1 RECIST v1.1
Clarify required imaging for the study.
For consistency between the 
protocol and the imaging 
manuals.
Section 5.1.2 Patient Reported 
Outcomes and Appendix D
Add  quality of life assessment EORTC 
QLQ-C30
Add Appendix D with sample 
questionnaire.
To include patient reported 
outcome measures and to align 
with revised 
objectives/endpoints.
Section 5.2.8 Safety Laboratory 
Assessments
Clarify peripheral blood lymphocytes 
subsets.
Clarify thyroid parameters to be 
collected.
Update for consistency across the 
protocol.
Per request of Health Canada.
Section 6.2 Method of Assigning 
Patient
Update to reflect changes to study 
design.
Consistency across protocol.
Section 6.6 Dose Modification and 
Toxicity Management
Add dose reduction guidelines and 
toxicity management for Cohort 2 (6 mg 
QW).
To ensure safety.
Section 7.1.1 Allowed Medications
Add guidelines for use of steroid in 
Cohort 2.
Prophylactic measure.
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Protocol Version 
& date
Rev.
Summary of Change
Rationale for Change
Section 8.4 Adverse Events of Special 
Interests
Add section on keratoacanthoma.
Based on regulatory 
requirements to disclose safety 
information.
Appendix B CYP3A4 Guidance
Clarify guidance.
Per request of the Netherlands 
Medical Research Ethics 
Committee (MREC).
Appendix E Country Specific 
requirements
Add country-specific requirements for 
contraception.
Appendix E (country specific 
requirements) was added to 
address requests from MHRA 
and ANSM regulatory agencies.
Appendix F  Protocol Amendment 
History and Summary of Changes
Move information about prior 
amendments to this location.
For readability.
Global
Update title to reflect changes to study 
design.
Align SoA to reflect changes in the 
protocol.
Terminology – use investigational 
product throughout for consistency
Update glossary.
For consistency across the 
protocol.
PRIOR AMENDMENTS
Protocol Version 
& date
Rev.
Highlight / Reason of Revision
Rationale for Change
V2.3, Amendment 
1.3 France-
Country Specific, 
15 August 2019
4.0
Section 4.1 (Inclusion criteria) and 
Section 7.4 (Contraception)
Clarify that use of contraception after 
last dose of investigational product will 
be 120 days (4 months).
Per request of ANSM- the 
French Regulatory Authority
V2.2, Amendment 
1.2 UK, 01 
August 2019
3.0
Section 4.1 (Inclusion criteria)
Clarify contraception language for male 
patients (inclusion criterion no. 10)
Per request of MHRA
V2.1, Amendment 
1.1 UK, 25 July 
2019
2.0
Protocol synopsis and Section 3 (Study 
design and schema) and Section 5.4 
(Biomarkers)
Per request of MHRA
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Document Version: 1.0
Effective Date: 23-Sep-2020
Document State: Effective (Controlled) 
CONFIDENTIAL
Page 112 of 118


Confidential
Protocol Version 
& date
Rev.
Highlight / Reason of Revision
Rationale for Change
Clarify that CE-marked device for NGS 
screening will be utilized.
Section 4.1 (Inclusion criteria) and 
Section 7.4 (Contraception)
Clarify contraception language 
Per request of MHRA
Section 1.3.2 (Clinical Studies)
Update study data per report
To align with study 
documents
Section 1.4 (Study Rationale)
Add nonclinical data
To provide supporting 
nonclinical data
Section 3 (Study design), synopsis and 
Schedule of Activities
Add prescreening procedures for NGS 
evaluation.
Clarify biopsy requirements for archival 
and fresh tumor tissue.
Clarify procedure for confirmation of 
response.
Shorten  recruitment duration to 18 
months
Requested by sites to ensure 
only patients with activating 
Notch mutation will proceed 
into screening.
To align with current 
recruitment forecast
Section 4.2 (exclusion)
Update exclusion criterion 1
Correct typos in exclusion criteria 12 
and 13 (f)
Eliminate exclusion of the number of 
prior therapies
(also in Section 7.1.2 prohibited 
concomitant medication)
Requested by sites, to clearly 
clarify which malignancies 
will be allowed into the 
study.
Requested by sites. They felt 
that ECOG status would 
correct for possible 
decreased performance status 
due to multiple prior 
therapies.
V2.0, Amendment 
1.0,
22 March 2019
CL-20-002
1.0
Section 5.2.6 and Schedule of Activities
Clarify that sites are provided with 
central  calibrated ECG machine.
Clarify when triplicate ECG are 
required.
To align with other study 
documents
To enhance safety 
monitoring 
Clinical Study Protocol AL-ACC-01
Document Number: CL6-0000866
Document Version: 1.0
Effective Date: 23-Sep-2020
Document State: Effective (Controlled) 
CONFIDENTIAL
Page 113 of 118


Confidential
Protocol Version 
& date
Rev.
Highlight / Reason of Revision
Rationale for Change
Section 5.2.8 (safety lab assessment)
Safety laboratories to be done locally 
Requested by sites, to allow 
faster review of data by 
investigator
To enhance safety 
monitoring and align with the 
AL101 investigator’s 
brochure.
Per request of sites and 
Health Canada.
Section 5.2.8 (safety lab assessment( 
and/or Schedule of Activities (SoA)
Clarify that

Hematology will be done at 
each study visit.

Chemistry will be conducted 
every week for the first 3 cycles 
and then every 2 weeks, with 
the exception of liver function 
tests which will be done weekly 
until week 32, and then every 2 
weeks thereafter
Add and modify laboratory tests to be 
done during the study:

Triglyceride monitoring during 
the study (screening and every 4 
weeks thereafter)

Peripheral blood lymphocyte 
subsets (at C1D1, C2D1 and 
every 8 weeks)

Thyroid panel (at C1D1 and 
every 12 weeks).

Serology tests at screening 
(HIV, hepatitis C RNA, 
hepatitis B surface antigen)

Pregnancy test (every 4 weeks 
while on treatment)

PSA (male only),

Creatinine clearance (screening)

HbA1c (at C1D1 and every 8 
weeks thereafter)

Blood sampling for biomarkers/ 
pharmacodynamics at C1D8
Separate biomarker collections into 2 
rows.
C1D8 timepoint will allow 
for evaluation of PD 
biomarkers at trough PK 
concentration after first dose, 
prior to second dose.
For clarity purposes.
Clinical Study Protocol AL-ACC-01
Document Number: CL6-0000866
Document Version: 1.0
Effective Date: 23-Sep-2020
Document State: Effective (Controlled) 
CONFIDENTIAL
Page 114 of 118


Confidential
Protocol Version 
& date
Rev.
Highlight / Reason of Revision
Rationale for Change
SoA
Clarify that ECG to be assessed 
throughout the study (at Screening, 
C3D1 and every 12 weeks)
To enhance safety 
monitoring and align with the 
AL101 investigator’s 
brochure
Section 5.1 (efficacy assessment)
Clarify procedure for confirmation of 
response
To align procedures as 
outlined in the independent 
Imaging Review Charter and 
per the RECIST 1.1 criteria 
with the clinical protocol 
Section 5.3 (popPK)
Clarify that patients in Stage 2 can be 
included in the PK analysis population
To ensure have sufficient 
sample size for population 
PK analysis
Section 5.4 (biomarkers)
Update to align with Laboratory Manual
To ensure consistency across 
study documents
Section 6.1 (investigational product)
Align preparation instructions with 
Study Pharmacy manual.
Clarify that only diethylhexyl 
phthalate-free bags and sets can be 
used to administer solutions.
To ensure consistency across 
study documents
Section 6.6 (dose modifications)
Align dose modifications for 
hematological Grade 4 toxicities with 
AL101 Investigator’s Brochure
Correct dose reduction instruction
To enhance safety 
monitoring and align with the 
AL101 investigator’s 
brochure
To ensure accuracy
Section 6.6.2 (diarrhea)
Clarify that for managing diarrhea, can 
use institutional protocol provided it 
meets standard practice
Requested by sites
Section 9.2 and Synopsis (Sample size 
consideration)
Clarify that new patients can be enroll 
while the data on the first 12 patients is 
maturing
Requested by sites
Section 9.8 and Synopsis 
Clarify assessment period for patients in 
Stage 1 (after at least 2 cycles and no 
more than 8 cycles) 
Per site request, limited the 
number of cycles for 
assessments in Stage 1 before 
proceeding to Stage 2
Clinical Study Protocol AL-ACC-01
Document Number: CL6-0000866
Document Version: 1.0
Effective Date: 23-Sep-2020
Document State: Effective (Controlled) 
CONFIDENTIAL
Page 115 of 118


Confidential
Protocol Version 
& date
Rev.
Highlight / Reason of Revision
Rationale for Change
Section 11.1.4 (DMC)
Clarify when DMC meets (after at least 
2 treatment cycles)
To align with initial on-
treatment radiographic 
imaging at 8 weeks
Appendix 3 RECIST
Clarify that CT is the preferred modality 
for radiographic imaging (except for 
bone metastases)
To ensure consistency across 
sites
Global: 

Update tissue archival 
collection to within 3 years and 
specify number of unstained 
slides required (25)
To ensure tissue is viable for 
study purposes

Align SoA with other protocol 
sections (e.g., visit window)

Clarify exploratory objectives

Add study name, ACCURACY

Update glossary

Delete BMS 906024 throughout

Minor consistency updates

Update links in Appendix A
V1.2 Canada 
Country-Specific 
Protocol,
25 September 
2018 
0.2
Section 6.6: Align dose modifications 
for hematological Grade 4 toxicities 
with AL101 Investigator’s brochure
To satisfy Health Canada 
request
Safety laboratories to be done locally 
Requested by sites, to allow 
faster review of data by 
investigator
V1.1 Canada 
Country-Specific 
Protocol,
20 September 
2018
0.1
Add and modify laboratory tests to be 
done during the study:

Triglyceride monitoring during 
the study (screening and every 4 
weeks thereafter)

Electrolytes (at C1D1 and every 
8 weeks thereafter)

Peripheral blood lymphocyte 
subsets (at C1D1, C2D1 and 
every 8 weeks)
To satisfy Health Canada 
request
Clinical Study Protocol AL-ACC-01
Document Number: CL6-0000866
Document Version: 1.0
Effective Date: 23-Sep-2020
Document State: Effective (Controlled) 
CONFIDENTIAL
Page 116 of 118


Confidential
Protocol Version 
& date
Rev.
Highlight / Reason of Revision
Rationale for Change

Thyroid panel (at C1D1 and 
every 12 weeks).

Serology tests at screening 
(HIV, hepatitis C RNA, 
hepatitis B surface antigen)
Pregnancy test (every 4 weeks while on 
treatment)
Add to Schedule of Activity:

PSA (male only),
Creatinine clearance (screening)
To align across the protocol 
(already mentioned in 
inclusion/exclusion)
Clarify that ECG to be assessed 
throughout the study (at C1D1 and 
every 12 weeks)
To satisfy Health Canada 
request
Original, V 1.0
19 July 2018
CC-18003
-
-
-
Clinical Study Protocol AL-ACC-01
Document Number: CL6-0000866
Document Version: 1.0
Effective Date: 23-Sep-2020
Document State: Effective (Controlled) 
CONFIDENTIAL
Page 117 of 118


This is a representation of an electronic record that was signed electronically and this page is the
manifestation of the electronic signatures.
Signatory Table
Action Name
User Name
Title
Signature Date
Send for Review (Written By)
Jeff Nieves
Exec Director Clinical Operations
16-Sep-2020 13:26 (GMT+2)
Review
Carmit Nadri-Shay
Director of Regulatory Affairs
16-Sep-2020 13:38 (GMT+2)
Review
Jeff Nieves
Exec Director Clinical Operations
16-Sep-2020 14:16 (GMT+2)
Send for Approval
Jeff Nieves
Exec Director Clinical Operations
22-Sep-2020 17:41 (GMT+2)
Approve
Amit Lahav
Director of QA
22-Sep-2020 18:47 (GMT+2)
Approve
Gary Gordon
CMO
22-Sep-2020 19:02 (GMT+2)
QA Approval - Skip Training
Amit Lahav
Director of QA
23-Sep-2020 08:08 (GMT+2)
Clinical Study Protocol AL-ACC-01
Document Number: CL6-0000866
Document Version: 1.0
Effective Date: 23-Sep-2020
Document State: Effective (Controlled) 
CONFIDENTIAL
Page 118 of 118

SAP_001.pdf: 
FORM BS-003-A                                     Confidential                                                                           V01.1  
SAP Template                                  Precision for Medicine                                                          Page 1 of 46  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan 
AL-ACC-101  
  
Version 2.0; 18 October 2022 
  
  
  
  
  
STATISTICAL ANALYSIS PLAN  
Ayala Pharmaceuticals, Inc.  
AL-ACC-101  
 
 
 
 
Protocol Title:  
A Phase 2, Open-Label, Multi-Center Study of AL101 in  
Patients with Adenoid Cystic Carcinoma (ACC) Bearing 
Activating Notch Mutations  
Protocol Version 
and Date:  
Version 4.0, Amendment 3.0; 27 August 2020  
Sponsor:  
Ayala Pharmaceuticals, Inc.  
1313 N. Market Street, Suite 5100,   
Wilmington, DE 19801, USA  
Prepared By:  
Gill Low  
Precision for Medicine  
80 George Street   
Edinburgh, United Kingdom   
EH2 3BU  
Document Version 
and Date:  
Version 2.0; 18 October 2022  
  


Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan 
AL-ACC-101  
  
Version 2.0; 18 October 2022 
  
FORM BS-003-A                                     Confidential                                                                           V01.1  
SAP Template                                  Precision for Medicine                                                          Page 2 of 46  
1 STATISTICAL ANALYSIS PLAN APPROVAL  
Sponsor:  
Ayala Pharmaceuticals, Inc.  
Clinical Protocol Number:  AL-ACC-101  
Protocol Title:  
A Phase 2, Open-Label, Multi-Center Study of AL101 
in Patients with Adenoid Cystic Carcinoma (ACC) 
Bearing Activating Notch Mutations  
Document File Name:  
Ayala_AL-ACC-101_SAP_v2.0_18Oct2022.pdf  
Document 
Version 
and 
Effective Date:  
Version 2.0; 18 October 2022  
Approved By:  
 
 
Gary Gordon, MD PhD  
Date Chief Medical Officer    
Ayala Pharmaceuticals, Inc.  
 
Principal Biostatistician  
 Precision for Medicine  
 
Ed Matthews  
Date Executive Director, Biostatistics  
 Precision for 
Medicine  
2 TABLE OF CONTENTS  
  
1  Statistical Analysis Plan Approval ................................................................................ 2 
2  Table of Contents ............................................................................................................ 2 
3  List of Abbreviations ...................................................................................................... 6 
  
    
24- Oct -2022 
  
    
Gill Low  
Date  
24- Oct -2022 
  
    
24- Oct -2022 


Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan 
AL-ACC-101  
  
Version 2.0; 18 October 2022 
  
FORM BS-003-A                                     Confidential                                                                           V01.1  
SAP Template                                  Precision for Medicine                                                          Page 3 of 46  
4 Introduction ..................................................................................................................... 8 
5 Study Objectives and Endpoints ................................................................................... 8 
5.1 Primary Study Objective and Endpoint .................................................................... 8 
5.2  Secondary Study Objectives and Endpoints ............................................................. 9 
5.3 Exploratory Study Objectives and Endpoints ......................................................... 10 
6 Investigational Plan ...................................................................................................... 11 
6.1 Overall Study Design ................................................................................................. 11 
6.2  Schedule of Assessments ........................................................................................... 14 
6.3  Treatment ................................................................................................................... 19 
6.3.1  Treatment Administered ........................................................................................ 19 
6.3.2  Method of Assigning Subjects to Treatment Groups .......................................... 19 
6.4  Efficacy and Safety Variables................................................................................... 19 
6.4.1  Description of Efficacy Variables ......................................................................... 19 
6.4.2  Description of Safety Variables ............................................................................. 26 
6.4.3  Description of Pharmacokinetic Variables .......................................................... 29 
6.5 Data Quality Assurance ............................................................................................. 29 
7 Statistical Methods ........................................................................................................ 30 
7.1 General Methodology ................................................................................................ 30 
7.1.1  Reporting Conventions .......................................................................................... 30 
7.1.2  Summarization by Visit ......................................................................................... 31 
7.1.3  Baseline Value ......................................................................................................... 31 
7.1.4  Data Handling Rules .............................................................................................. 31 
7.1.5  Standard Calculations ........................................................................................... 31 
7.2  Analysis Populations ................................................................................................. 32 
7.3  Study Subjects ........................................................................................................... 33 
7.3.1 Disposition of Subjects ............................................................................................ 33 
7.3.2 Protocol Deviations ................................................................................................. 33 
7.4 Demographic and Other Baseline Characteristics.................................................. 33 
7.4.1 Demographics .......................................................................................................... 33 
7.4.2  Baseline Characteristics ........................................................................................ 33 
7.4.3 ACC Disease History .............................................................................................. 34 
7.4.4 Prior Cancer Treatment ......................................................................................... 34 
7.4.5  Medical History ...................................................................................................... 35 
7.5 Efficacy Evaluation .................................................................................................... 35 
7.5.1 Datasets Analyzed ................................................................................................... 35 
7.5.2 Primary Efficacy Endpoint Analysis Methods ..................................................... 36 
7.5.3 Secondary Endpoint Analysis Methods ................................................................ 37 
7.5.4  Statistical/Analytical Issues ................................................................................... 40 
7.6  Population Pharmacokinetic Analysis ..................................................................... 43 
7.7  Exploratory Biomarker Analysis ............................................................................. 43 
7.8  Safety Evaluation ...................................................................................................... 43 
7.8.1  Extent of Exposure and Treatment Compliance ................................................. 43 
7.8.2  Adverse Events ....................................................................................................... 44 


Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan 
AL-ACC-101  
  
Version 2.0; 18 October 2022 
  
FORM BS-003-A                                     Confidential                                                                           V01.1  
SAP Template                                  Precision for Medicine                                                          Page 4 of 46  
7.8.3  Deaths, Other Serious Adverse Events, and Other Significant  ......................... 45 
Adverse Events ............................................................................................... 45 
7.8.4  Clinical Laboratory Evaluation ............................................................................ 45 
7.8.5  Vital Signs, Physical Findings, and Other Observations Related to Safety ...... 46 
7.9  Determination of Sample Size .................................................................................. 48 
7.10  Changes in the Conduct of the Study or Planned Analyses ................................ 49 
8  Reference List ............................................................................................................... 50 
 
  
  
  
 


Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan 
AL-ACC-101  
  
Version 2.0; 18 October 2022 
  
FORM BS-003-A                                     Confidential                                                                           V01.1  
SAP Template                                  Precision for Medicine                                                          Page 5 of 46  
TABLE OF TABLES  
Table 1  
List of Abbreviations .................................................................................6  
Table 2  
Schedule of Assessments ..........................................................................13  
Table 3  
RECIST 1.1 Evaluation of Target Lesions: ...........................................18  
Table 4  
RECIST 1.1 Evaluation of Non-target Lesions: ....................................18  
Table 5  
RECIST 1.1 Overall Response: ..............................................................18  
Table 6           Best Overall Response When Confirmation of Complete Response and  
Partial Response is Required ..................................................................19  
Table 7  
Determining Date of Progression or Censoring for PFS and DOR  
Analysis .....................................................................................................20  
Table 8  
EORTC QLQ-C30 Scales ........................................................................22  
  
  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 6 of 46  
3 LIST OF ABBREVIATIONS   
Table 1  
List of Abbreviations   
  
 
ACC  
Adenoid Cystic Carcinoma  
AE  
Adverse Event  
AESI  
Adverse Event(s) of Special Interest  
ALT  
Alanine Aminotransferase  
aPTT  
Activated Partial Thromboplastin Time  
AST  
Aspartate Aminotransferase  
BMI  
Body Mass Index   
BOR  
Best Overall Response   
BUN  
Blood Urea Nitrogen   
C1D1  
Cycle 1, Day 1  
CBC  
Complete Blood Count  
CI  
Confidence Interval  
CR  
Complete Response  
CrCl  
Creatinine Clearance  
CSR  
Clinical Study Report  
CT  
Computed Tomography  
CTCAE  
Common Terminology Criteria for Adverse Events (version 5.0)  
DCR  
Disease Control Rate (CR + PR + SD)  
DILI  
Drug-induced Liver Toxicity  
DMC  
Data Monitoring Committee   
DOR  
Duration of Response  
ECG  
12-Lead Electrocardiogram   
ECOG  
Eastern Cooperative Oncology Group  
eCRF  
Electronic Case Report Form  
EORTC-QLQ-C30  
European Organization for Research and Treatment of Cancer
Quality of Life Questionnaire 30 Questions  
EOS  
End of Study  
FDA  
Food and Drug Administration  
FFPE  
Formalin-Fixed Paraffin Embedded  
HCV  
Hepatitis C  
Abbreviation  
Definition  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 7 of 46  
 
HIV  
Human Immunodeficiency Virus   
ICF  
Informed Consent Form  
ICH  
International Council for 
Harmonisation   
ICR  
Independent Central Review   
IHC  
Immunohistochemistry   
IV  
Intravenous  
LDH  
Lactate Dehydrogenase  
MDA  
MD Anderson  
MedDRA  
Medical Dictionary for Regulatory 
Activities  
MRI  
Magnetic Resonance Imaging  
NCI  
National Cancer Institute  
NGS  
Next Generation Sequencing   
NICD  
Notch Intracellular Domain   
ORR  
Objective Response Rate  
OS  
Overall Survival  
PD  
Progression of Disease  
PD-L1  
Programed Death Ligand  
PET  
Positron Emission Tomography  
PFS  
Progression Free Survival  
PK  
Pharmacokinetics  
PP  
Per-Protocol   
PR  
Partial Response  
PT (AE)  
Preferred Term  
PT (lab)  
Prothrombin Time  
PTT  
Partial Thromboplastin Time   
QoL  
Quality of Life  
QW  
Every week  
RECIST  
Response Evaluation Criteria in Solid 
Tumors  
RS  
RawScore  
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SD (clinical)  
Stable Disease  
SD (statistics)  
Standard Deviation  
Abbreviation  
Definition  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 8 of 46  
TEAE  
Treatment Emergent Adverse Event  
TTR  
Time to Response  
ULN  
Upper Limit of Normal  
Abbreviation  
Definition  
WHO  
World Health Organization  
4 INTRODUCTION  
The purpose of this statistical analysis plan (SAP) is to provide comprehensive and 
detailed descriptions of the methods and presentation of data analyses proposed for Ayala 
Pharmaceuticals, Inc. Protocol AL-ACC-101 (A Phase 2, Open-Label, Single-Arm,  
Multi-Center Study of AL101 in Patients with Adenoid Cystic Carcinoma [ACC] Bearing 
Activating Notch Mutations). Descriptions of planned analyses are provided to avoid post 
hoc decisions that may affect the interpretation of the statistical analysis. The statistical 
methods applied in the design and planned analyses of this study are consistent with the 
International Council for Harmonisation (ICH) guideline Statistical Principles for 
Clinical Trials (E9) (1998).   
This SAP will be finalized prior to database lock to provide full details, including 
templates for tables, listings, and figures, to be presented in the clinical study report 
(CSR). Where there are differences between the protocol and the SAP, the SAP will 
supersede the protocol. Any changes between the statistical methods provided in the 
clinical study protocol and this SAP will be explained herein; any changes or deviations 
from this SAP relative to the final analysis will be fully documented in the CSR. Minor 
changes or deviations from the templates for tables, figures, and listings need not be 
documented in the CSR.  
The SAP has been updated between the dry-run and database lock to align with what has 
now been agreed as being required with regards to the CSR. Several outputs which were 
not explicitly mentioned in the protocol but were added prior to finalization of version 
1.0 of the SAP have been removed since these are no longer required for the CSR. An 
additional analysis population based on central review of the scans has been added for the 
analysis based on the central review data. No changes were made with regards to 
analyses planned in the protocol.  
5 STUDY OBJECTIVES AND ENDPOINTS  
5.1  
Primary Study Objective and Endpoint  
  
Objective  
Endpoint  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 9 of 46  
 To assess the clinical activity of AL101 
using radiographic assessments and 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 in ACC  
patients with activating Notch 
mutations  
 Objective response rate (ORR; complete 
response [CR] and partial response 
[PR]) by RECIST v1.1 as determined 
by Investigator review. For patients 
with bone exclusive disease, the 
modified MD Anderson (MDA)  
 
bone criteria will be used to access 
response.  
  
5.2  
Secondary Study Objectives and Endpoints  
  
Objectives  
Endpoints  
 Clinical activity assessments  
• Duration of response (DOR) by 
Investigator review based on RECIST 
v1.1.  
• Progression free survival (PFS) by 
Investigator review based on RECIST 
v1.1.  
• Overall survival (OS).  
• Time to response (TTR) by  
Investigator review based on RECIST 
v1.1.  
• Disease control rate (DCR) by 
Investigator review based on RECIST 
v1.1.  
 To assess quality of life (QoL) in ACC 
patients with activating Notch 
mutations.  
 Change from baseline in European 
Organization for Research and  
Treatment of Cancer Quality of Life 
Questionnaire 30 Questions (EORTC 
QLQ-C30).  
 To confirm safety and tolerability of 
AL101 in ACC patients with activating  
Notch mutations.  
• Frequency, duration and severity of 
adverse events (AEs) and serious 
adverse events (SAEs).  
• Incidence of clinically significant 
laboratory abnormalities; safety 
laboratory evaluations includes 
complete blood count (CBC), blood 
biochemistry and urinalysis.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  
age 10 of 
46  
 To obtain a set of population parameters 
and to identify covariates that affect 
systemic exposure to AL101 and 
metabolite(s).  
 PK parameters including AUC, Cmax,  
Tmax, and T1/2  
  
For AL101 and metabolite(s), one- and 
two compartment linear models will be 
applied to the data  
  
5.3  
Exploratory Study Objectives and Endpoints  
  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 11 of 
46  
Objectives  
Endpoints  
• To establish correlation between 
positive Notch1 intracellular domain 
(NICD1) stain and Notch1 activating 
mutations.  
• To establish the correlation between 
mutations in Notch and associated 
genes and response or resistance to 
investigational product.  
• Predictive biomarkers of response or 
resistance to the investigational 
product will be explored:  
- 
Immunohistochemistry (IHC): 
Tumor specimens will be 
stained for NICD1 and other 
biomarkers such as, but not 
limited to: programmed death 
ligand (PD-L1), Ki-67 and  
FBXW7.  
- 
Next Generation Sequencing 
(NGS): Mutational analysis 
will be performed in tissues 
samples as well as in cell-free 
DNA (cfDNA).  
• Pharmacodynamic markers indicative 
of drug activity will be measured, 
including HES-1 and others such as 
but not limited to: HES-4, HES-5, 
HEY-1, 2, HEYL, HIF1 alpha, and 
others.  
  
6 INVESTIGATIONAL PLAN  
6.1  
Overall Study Design  
This is a Phase 2, non-comparative, open-label, multicenter study of AL101 in patients 
with recurrent or metastatic ACC who harbor NOTCH 1,2,3,4 activating mutations.  
The study includes 2 cohorts, ran in a sequential fashion:  
• 
Cohort 1 – AL101 4 mg once weekly (QW) intravenously (IV)  
• 
Cohort 2 – AL101 6 mg QW IV  
Cohort 1 will continue to enroll to reach up to a maximum of 45 patients. Cohort 2 will 
open for enrollment up to a maximum of 42 patients. Prior to entering the study, to 
determine eligibility, potential candidates will undergo pre-screening assessment and 
confirmation for the presence of activating Notch mutations. Available mutation status 
from prior tests with any commercially available or locally developed NGS assay are 
acceptable. In Europe any commercially available CE marked device shall be used.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 12 of 
46  
If historical genotyping results are not available, testing will need to be conducted during 
prescreening using a laboratory developed or commercially available NGS assay to 
identify and confirm an activating Notch mutation. Any newly characterized mutation 
(such as tandem duplication, variant allele frequency, variants of unknown significance, 
etc.), will be evaluated with the Sponsor on a case-by-case basis. Pre-screening 
studyspecific assessments may be done while potential candidates are on other therapy 
provided that a separate pre-screening informed consent form is signed.  
Patients with activating Notch mutations will then undergo screening assessments to 
determine study eligibility over a 28-day Screening period. Enrollment of patients with 
bone exclusive disease should be discussed and approved by the Sponsor’s Medical 
Monitor before enrollment. For all patients, prior treatments and responses to such 
treatments, including radiological images and reports, within a year of study entry will 
be collected as part of the medical history; for patients who are currently enrolled, this 
information will be collected retrospectively.  
Starting on Cycle 1, Day 1, eligible patients will receive AL101, either 4 mg QW IV in 
Cohort 1or 6 mg QW IV in Cohort 2, on Days 1, 8, 15, and 22 of each 28-day cycle until 
disease progression, unacceptable toxicity, or consent withdrawal. For patients with 
radiological progression, investigational product may be continued as long as the patient 
is having clinical benefit, is agreed to by the patient and physician and approved by the 
Sponsor’s Medical Monitor.  
Paired tumor biopsies will be collected at screening (fresh or archival5 within 3 years) 
and on treatment at Cycle 4 Day 1 ±28 days provided medically safe and not 
contraindicated. Samples will be sent to a central vendor for NGS analysis. Tumor 
Formalin-fixed paraffin embedded (FFPE) slides will be evaluated by IHC for NICD1 
stain. On the day of the on-treatment biopsy, blood will also be drawn for PK and 
biomarker assessments.  
During the Treatment period, patients will undergo radiographic assessments every 8 
weeks (±3 days) for review by the Investigator. Scans will be collected and held for 
possible future retrospective evaluation by independent central review (ICR). Other 
assessments will be done as specified in Schedule of Activities (SoA; Table 1), including 
safety and exploratory biomarkers.  
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.  
All patients will undergo end of study (EOS) visit 30 days post last treatment and be 
contacted by phone every 3 months to determine survival status. In patients who 
discontinued investigational product due to toxicity, radiographic imaging will be done 


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
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SAP Template                                     Precision for Medicine                                                     P  age 13 of 
46  
every 3 months until disease progression or until patient initiates another anti-cancer 
therapy.  
Study participation for each patient consists of:  
• 
Screening period: up to 28 days  
• 
Treatment period: Weekly treatment, until disease progression6, unacceptable 
toxicity, or consent withdrawal  
• 
EOS: 30 days after the last administration of investigational product.  
• 
Long term follow-up: Every 3 months. 


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
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SAP Template                                     Precision for Medicine                                                     P age 14 of 46  
6.2  
Schedule of Assessments  
Table 2  
Schedule of Assessments  
  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
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SAP Template                                     Precision for Medicine                                                     P age 15 of 46  
  
  
  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
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SAP Template                                     Precision for Medicine                                                     P age 16 of 46  
  
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; 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 confirm the presence of activating Notch mutations. Available genotyping results 
from a laboratory developed or commercially available NGS assay are acceptable. If historical genotyping results are not available, patient must sign prescreening ICF, and 
testing will need to be conducted during pre-screening using a laboratory developed or commercially available NGS assay. Available NGS test results will be shared in the 
Preidentification form and response confirming activating Notch mutation is required before entering screening. Any newly characterized mutation (such as tandem duplication, 
variant allele frequency, variants of unknown significance, etc.), will be evaluated with the Sponsor on a case-by-case basis.  
c. Paired 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 3 
years), and at Cycle 4 Day 1 ±28 days or earlier if the patient progressed (fresh sample, provided medically safe and not contraindicated). If an archival tumor block or 25 
unstained slides are not available, the patient will be required to have a fresh tumor sample obtained at screening. Attempts should be made to biopsy lesions which are not 
considered to be “target lesions” per RECIST 1.1. criteria.  
d. Full physical examination at baseline; targeted physical examination at other time points.  
e. Complete blood count (CBC) includes hemoglobin, hematocrit, platelet count, WBC count, and absolute differential count.  
f. Chemistry includes glucose, blood urea nitrogen (BUN), creatinine, total bilirubin (a direct bilirubin should be obtained if the total bilirubin level is >1.5 times ULN), albumin, 
AST (SGOT), ALT (SGPT), alkaline phosphatase (ALP), lactate dehydrogenase, electrolytes (sodium, potassium, chloride, calcium, magnesium, and phosphorus. Creatinine 
clearance (CrCl) will be conducted at screening only; Calculation of CrCl will be based on acceptable institution standard). 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 2 weeks, with the exception of liver function tests (AST/ALT/ALP/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…).  


  
  
Ayala Pharmaceuticals, Inc.  
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j. Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) performed at Screening and as clinically indicated.  
k. 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 centrally. Clinically significant ECG abnormalities will be recorded on the eCRF. Triplicate ECGs, at least 3 minutes apart, will be performed if QTcF is > 500 msec 
or if the Investigator identifies an ECG finding (for example QT interval prolonged or cardiac arrythmia) that is an adverse event and related to investigational product. l. Pre-
menopausal female patients of childbearing potential only. Urine or serum pregnancy tests are acceptable.  
m. CT or MRI with contrast, of the neck, chest, abdomen, and pelvis are acceptable (PET/CT is not allowed for study assessments, unless CT is done with IV contrast). Images 
will be repeated every 8 weeks (±3 days) during treatment period until disease progression. During the Long-term Follow-up visit, only in patients who discontinued 
investigational product due to toxicity, radiographic imaging will be done every 3 months until disease progression or until patient initiates another anti-cancer therapy. The same 
radiographic technique of each region must be used consistently throughout the study. Refer to Imaging Manual. 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. n. 
Quality of life questionnaire will be administered every 4 weeks before investigational product administration or receipt of radiological imaging results  
o. 
For blood mRNA pharmacodynamic biomarker assessments, blood will be drawn on C1D1 and C1D22 at pre-dose (within 1 hour before start of dose), 7 hours (±1 hour, 
and 24-48 hours after start of infusion (±1 hour), C1D8 pre-dose (within 1 hour before start of dose), C2D1 pre-dose (within 1 hour before start of dose), every odd cycle Day 22 
predose (within 1 hour before start of dose), and at confirmed progression. In addition, a blood sample will be collected on the day of the on-treatment biopsy (Cycle 4, Day 1 ±28 
days).  
p. 
For blood cfDNA biomarker assessments, blood will be drawn on C1D1 and C2D1 at pre-dose (within 1 hour before start of dose), and every odd cycle Day 22 pre-dose 
(within 1 hour before start of dose), and at confirmed progression. In addition, a blood sample will be collected on the day of the on treatment biopsy (Cycle 4, Day 1 ±28 days). q. 
During Cycle 1, population PK blood samples will be collected as follows:  
Dose No. in a 
given cycle  
Cycle / Day  
 Hours Relative to Dose 
(Window)  
1  
Cycle 1 / Day1 
1  
Pre-dose (within 1 hour 
before start of dose)  
End-infusion (within 10 
minutes of infusion end)   
2 hours after start of 
infusion (± 30 minutes)  
4 hours after start of 
infusion (± 1 hour)   
7 hours after start of 
infusion (±1 hour)  
1  
Cycle 1 / Day 2 
or 3  
2 or 3  
24 - 48 hours after start of 
infusion (±1 hour)  
2  
Cycle 1 / Day 
8  
8  
Pre-dose (within 1 hour 
before start of dose)  
3  
Cycle 1 / Day 
15  
15  
Pre-dose (within 1 hour 
before start of dose)  
Nominal   Day   


  
  
Ayala Pharmaceuticals, Inc.  
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4  
Cycle 1 / Day 
22  
22  
Pre-dose (within 1 hour 
before start of dose)  
End-infusion (within 10 
minutes of infusion end)   
2 hours after start of 
infusion (±30 minutes)  
4 hours after start of 
infusion (± 1 hour)   
7 hours after start of 
infusion (± 1 hour)  
4  
Cycle 1 / Day 23 or 
Day 24  
23 or 24  
24 - 48 hours after start of 
infusion (±1 hour)  
4 Cycle 2 / Day 1 29 End of Cycle 1 (pre-dose Cycle 2) (within 1 hour   
 
 
before start of dose)    
In addition, a PK sample will be collected on the day of the on-treatment biopsy (Cycle 4, Day 1 ±28 days).   


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
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Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
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SAP Template                                     Precision for Medicine                                                     P  age 19 of 46  
6.3  
Treatment  
6.3.1  
Treatment Administered  
AL101 will be administered IV at the dose of 4 mg every 7 days (±2 day; QW) in Cohort 
1 and at the dose of 6 mg every 7 days (±2 day; QW) in Cohort 2 over 28-day cycles until 
disease progression, unacceptable toxicity, or consent withdrawal. For patients with 
radiological progression, investigational product can be continued as long as the patient is 
having clinical benefit, is agreed to by the patient and physician and approved by the 
Sponsor’s Medical Monitor.   
AL101 will be administered using an IV infusion pump over 60 minutes; time windows 
of -5 minutes to +10 minutes are permitted.  
AL101 injection has been developed as a single-use sterile solution (1.2 mg/mL) for IV 
administration in clinical studies; each vial contains 5 mL (equivalent of 6 mg per vial). It 
is formulated as a sterile concentrate containing Cremophor® and ethanol and will be 
diluted with 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose 
Injection, USP (D5W) to concentrations between 0.01 mg/mL and 0.06 mg/mL. In order 
to reduce the risk of infusion reactions caused by Cremophor, use premedication per 
institution guidelines such as H1- and H2-blockers (diphenhydramine and ranitidine or 
equivalents) or dexamethasone will be given.  
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 electronic case report form (eCRF).  
6.3.2  
Method of Assigning Subjects to Treatment Groups  
This is an open-label design, with all patients assigned sequentially to 1 of 2 cohorts and 
receive AL101 monotherapy. Cohort 1 enrolled up to a maximum of 45 patients and 
cohort 2 enrolled up to a maximum of 42 patients.  
6.4  
Efficacy and Safety Variables  
6.4.1  
Description of Efficacy Variables  
6.4.1.1  
Primary Efficacy Variables  
The primary efficacy endpoint is the objective response rate (ORR).  
ORR is defined as the proportion of subjects who have a best overall response (BOR) of 
complete response (CR) or partial response (PR) as determined by Investigator review 


  
  
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using RECIST v1.1 (Protocol Appendix C) or modified MDA bone criteria for subjects 
with bone-exclusive disease (Protocol Appendix C, Table 11).  
BOR is defined as the best response recorded between the date of first infusion of 
investigational product and the date of subsequent anti-cancer therapy. A BOR of CR or 
PR requires confirmation of the assessment at least 4 weeks later. A BOR of SD requires 
the assessment to be recorded no less than 4 weeks after the start of study medication.  
RECIST 1.1 (Eisenhauer 2009) will be used to determine response at each post-baseline 
time point. Assessment of target lesions, non-target lesions, new lesions, and overall 
response will be assigned as described in Table 3, Table 4 and Table 5. Table 6 describes 
the derivation of best overall response from overall response assessments at each visit.  
  
Table 3  
RECIST 1.1 Evaluation of Target Lesions:  
Response  Definition  
CR  
Disappearance of all target lesions. Any pathological lymph nodes must 
have reduction in short axis to < 10 mm.  
PR  
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters.  
PD  
At least a 20% increase in the sum of the diameters, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. The 
appearance of one or more new lesions is also considered progression.   
SD  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters on study.  
  
Table 4  
RECIST 1.1 Evaluation of Non-target Lesions:  
Response  Definition  
CR  
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).  
SD   
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits.  
PD  
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.  
  
Table 5  
RECIST 1.1 Overall Response:  


  
  
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Target lesions  
Non-Target lesions  
New Lesions  
Overall response  
CR  
CR  
No  
CR  
CR  
Non-CR/non-PR  
No  
PR  
CR  
Not evaluated  
No  
PR  
PR  
Non-PD or not all evaluated  
No  
PR  
SD  
Non-PD or not all evaluated  
No  
SD  
Not all evaluated  
Non-PD  
No  
NE  
PD  
Any  
Yes or No  
PD  
Any  
PD  
Yes or No  
PD  
Any  
Any  
Yes  
PD  
Table 6           Best Overall Response When Confirmation of Complete Response and  
Partial Response is Required   
Overall  
Response First 
Timepoint  
Overall  
Response  
Subsequent  
Timepoint  
Best Overall Response  
CR  
CR  
CR  
CR  
PR  
SD, PD or PRa  
CR  
SD  
SD provided minimum criteria for SD duration was met, 
otherwise, PD  
CR  
PD  
SD provided minimum criteria for SD duration was met, 
otherwise, PD  
CR  
NE  
SD provided minimum criteria for SD duration was met, 
otherwise, NE  
PR  
CR  
PR  
PR  
PR  
PR  
PR  
SD  
SD  
PR  
PD  
SD provided minimum criteria for SD duration was met, 
otherwise, PD  
PR  
NE  
SD provided minimum criteria for SD duration was met, 
otherwise, NE  
NE  
NE  
NE  
a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not 


  
  
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CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.  
CR=complete response; NE=not evaluable; PD=progressive disease; PR=partial response; SD=stable disease. PD: 
progressive disease.  SD: requires a minimum duration of 4 weeks from the start of treatment.  
  
As part of the sensitivity analysis, BOR and ORR will also be derived as follows:  
• 
As above but where confirmation of PR/CR is not required.  
• 
As above but based on central review rather than Investigator review.  
• 
As above but based on central review rather than Investigator review and where 
confirmation of PR/CR is not required.  
6.4.1.2  
Secondary Efficacy Variables  
Secondary efficacy endpoints include the following:  
Duration of Response (DOR): defined as the time interval from the initial confirmed 
response of CR or PR to the earlier of the first documentation of disease progression (per 
RECIST v1.1 or modified MDA criteria) or death from any cause, as determined by 
Investigator review. DOR will be calculated in months as (date of disease progression or 
death/censoring – date of initial response + 1) / 30.4375.   
For DOR (and PFS) the date of progression or death and censoring will be based on the 
Food and Drug Administration (FDA) guidance Clinical Trial Endpoints for the Approval 
of Cancer Drugs and Biologics (May 2007), as defined in Table 7.  
Table 7  
Determining Date of Progression or Censoring for PFS and DOR  
Analysis  
Situation  
Date of Progression or Censoring  
Outcome  
Alive and without documentation of 
disease progression.   
Date of last disease assessment. All patients still 
alive and without documentation of disease will 
be censored as of July 31, 2022.   
Censored   
Treatment discontinuation for 
undocumented progression   
Date of last disease assessment   
Censored   
Treatment discontinuation for toxicity 
or other reason   
Date of last disease assessment   
Censored   
Other anticancer treatment started 
before documentation of disease 
progression or death   
Date of last disease assessment prior to start of 
other anticancer treatment   
Censored   


  
  
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Death before first disease assessment   
Date of death   
Progressed   
Death or disease progression between 
planned disease assessments   
Date of death or first disease assessment 
showing disease progression, whichever occurs 
first  
Progressed   
Death or progression after more than 
one missed disease assessment   
Date of last disease assessment visit without 
documentation of disease progression that is 
before the first missed visit   
Censored   
  
As part of the sensitivity analysis, DOR will also be derived as follows:  
• 
As above but where confirmation of PR/CR is not required.  
• 
As above but based on central review rather than Investigator review.  
• 
As above but based on central review rather than Investigator review and where 
confirmation of PR/CR is not required.  
Progression-Free Survival (PFS): defined as the interval from the start of investigational 
product to the earlier of the first documentation of disease progression (per RECIST v1.1 
or modified MDA criteria) or death from any cause, as determined by Investigator review. 
Progression-free survival will be defined in months as: (date of progression or 
death/censoring – date of first infusion + 1) / 30.4375.  
Patients without disease progression or death will be censored as per Table 7.  
As part of the sensitivity analysis, PFS will also be derived as follows:  
• 
As above but based on central review rather than Investigator review.  
  
Overall Survival (OS):  defined as the time from the date of start of treatment to the date 
of death from any cause. Subjects with no documentation of death will be censored at the 
last date known to be alive, per the data collection. Sites will be asked to search public 
registries for any possible death dates for subjects who withdrew consent from the study  
(as per FDA Guidance for Sponsors, Clinical Investigators, and IRBs  
Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials). Where it 
is possible for this search to be done, any deaths found will be included in the analysis. 
Overall survival time will be calculated in months as (date of death/censoring – date of 
first infusion + 1) / 30.4375.   
As part of the sensitivity analysis, OS will also be derived as follows:  


  
  
Ayala Pharmaceuticals, Inc.  
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• 
As above but where date of first diagnosis of recurrent or metastatic disease is 
used instead of date of first infusion.  
• 
As above but where date of initial ACC diagnosis is used instead of date of first 
infusion.  
  
Time to Response (TTR): defined as the interval from the start of investigational product 
to the initial (subsequently confirmed) response of CR or PR (per RECIST v1.1 or 
modified MDA criteria), as determined by Investigator review. TTR will be calculated in 
months as (date of initial response/censoring – date of first infusion + 1) / 30.4375.  
Patients without response will be right censored at their last tumor assessment.   
As part of the sensitivity analysis, TTR will also be derived as follows:  
• 
As above but where confirmation of PR/CR is not required.  
• 
As above but based on central review rather than Investigator review.  
• 
As above but based on central review rather than Investigator review and where 
confirmation of PR/CR is not required.  
  
Disease control rate (DCR): defined as the proportion of subjects who have a BOR of CR, 
PR or SD as determined by Investigator review using RECIST v1.1 (per RECIST v1.1 or 
modified MDA criteria). A BOR of CR or PR requires confirmation of the assessment at 
least 4 weeks later. A BOR of SD requires the assessment to be recorded no less than 4 
weeks after the start of study medication.  
As part of the sensitivity analysis, DCR will also be derived as follows:  
• 
As above but where confirmation of PR/CR is not required.  
• 
As above but based on central review rather than Investigator review.  
• 
As above but based on central review rather than Investigator review and where 
confirmation of PR/CR is not required.  
European Organization for Research and Treatment of Cancer Quality of Life  
Questionnaire (EORTC QLQ-C30): quality of life, as measured by EORTC QLQ-C30, 
will be assessed during the study every 4 weeks, prior to investigational product 
administration. The QLQ-C30 questionnaire is composed of 5 multi-item scales 
(physical, role, social, emotional and cognitive functioning) and 9 single items (pain, 
fatigue, financial impact, appetite loss, nausea/vomiting, diarrhea, constipation, sleep 


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
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disturbance and quality of life) (Kyriaki, 2001). It is validated and reliable and has been 
used successfully in various types of cancer, including head and neck cancer.  
Individual items contribute to the scales as shown below:  
Table 8  
EORTC QLQ-C30 Scales  
  
Scale  
Number of 
Items  
Item Range*  
Item  
Numbers  
Global health status / QoL  
Global health status / QoL 
(revised)†  
 
QL2  
 
2  
 
6  
 
29, 30  
Functional scales  
Physical functioning (revised) †  
 
PF2  
 
5  
 
3  
 
1 to 5  
Role functioning (revised) †  
RF2  
2  
3  
6, 7  
Emotional functioning  
EF  
4  
3  
21 to 24  
Cognitive functioning  
CF  
2  
3  
20, 25  
Social functioning  
SF  
2  
3  
26, 27  
Symptom scales / items Fatigue  
 
FA  
 
3  
 
3  
 
10, 12, 18  
Nausea and vomiting  
NV  
2  
3  
14, 15  
Pain  
PA  
2  
3  
9, 19  
Dyspnoea  
DY  
1  
3  
8  
Insomnia  
SL  
1  
3  
11  
Appetite loss  
AP  
1  
3  
13  
Constipation  
CO  
1  
3  
16  
Diarrhoea  
DI  
1  
3  
17  
Financial difficulties  
FI  
1  
3  
28  
* Item range is the difference between the possible maximum and the minimum response to individual 
items; most items take values from 1 to 4, giving range = 3.  
† (revised) scales are those that have been changed since version 1.0, and their short names are indicated in 
this manual by a suffix “2” – for example, PF2.  
For all scales, the RawScore (RS) is the mean of the component items:  
𝑅𝑆 = (𝐼1 + 𝐼2 + ⋯ + 𝐼𝑛)/𝑛  
A linear transformation to 0-100 is then applied to obtain the score S:  
Functional scales:  
(𝑅𝑆 − 1) 
𝑆 = {1 − 
} × 100  


  
  
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𝑅𝑎𝑛𝑔𝑒 
Symptom scales / items and global health status / quality of life (QoL):  
𝑅𝑆 − 1 
𝑆 = {
} × 100  
𝑅𝑎𝑛𝑔𝑒 
Range is the difference between the maximum possible value of RS and the minimum 
possible value. The QLQ-C30 has been designed so that all items in any scale take the same 
range of values. Therefore, the range of RS equals the range of the item values. Most items 
are scored 1 to 4, giving range = 3. The exceptions are the items contributing to the global 
health status / QoL, which are 7-point questions with range = 6.  
The scales will be computed only if at least half of the required responses are non-missing. 
For example, role functioning (RF) and cognitive functioning (CF) each contain 2 items, 
and so these scales can be estimated whenever one of their constituent items is present; 
physical functioning contains 5 items, and so at least 3 need to have been completed. None 
of the single-item measures will be calculated if the question has not been answered.  
  
6.4.2  
Description of Safety Variables  
6.4.2.1  
Adverse Events  
Adverse events (AEs) will be assessed and recorded at all study visits throughout the 
study from informed consent signing through EOS visit (30 days following cessation of 
investigational product). AEs are described in detail in Section 8.1 of the protocol.   
Treatment-emergent adverse events (TEAEs) are defined as those AEs with onset during 
or after the first infusion of investigational product until 30 days after the last infusion of 
investigational product or existing events that worsened after the first infusion during the 
study until 30 days after the last infusion of investigational product.   
Events reported with a partial onset date (eg, month and year are reported but the day is 
missing) will be considered treatment-emergent if it cannot be confirmed that the event 
onset was prior to the first dose of investigational product based on the available date 
entries.  
Verbatim terms on case report forms will be mapped to preferred terms and system organ 
classes using the Medical Dictionary for Regulatory Activities (MedDRA, version 23.0).   
Severity of the TEAEs will be graded based on NCI Common Terminology Criteria for  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 27 of 46  
Adverse Events (CTCAE), version 5.0 (Nov 2017). Grades will be presented as mild 
(Grade 1), moderate (Grade 2), severe or medically significant (Grade 3), life-threatening 
(Grade 4) or death (Grade 5).  
Adverse events of special interest (AESI) include hepatic function abnormalities 
(hepatotoxicity), colitis, infusion reactions (including anaphylaxis), Keratoacanthoma and 
potential drug-induced liver injury (DILI).  
6.4.2.2  
Medical History and Concomitant Medications  
Any clinically significant diseases 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 regimens for ACC. 
Verbatim terms on case report forms will be mapped to preferred terms and system organ 
classes using the Medical Dictionary for Regulatory Activities (MedDRA, version 23.0) 
and will be summarized by SOC and PT.  
  
  
Abnormal physical examination finding and/or the diagnosis of concomitant disease 
resulting from assessments at Screening will also be 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.   
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 investigational product will be 
recorded. Concomitant medications will be coded according to the WHO Drug dictionary 
and will be summarized according to the coded terms.  
6.4.2.3  
Eastern Cooperative Oncology Group Performance Status  
The Eastern Cooperative Oncology Group (ECOG) Performance Status will be collected 
at all study visits and be used to assess the subjects’ performance status.   
6.4.2.4  
Vital Signs  
Vital signs 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.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 28 of 46  
6.4.2.5  
12-Lead Electrocardiogram (ECG)   
Single 12-Lead ECG will be performed at the Screening, every 12 weeks, and the End of 
Study visits. Twelve-Lead ECG will be obtained using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.  
Triplicate ECGs, at least 3 minutes apart, will be performed if QTcF is > 500 msec or if the 
Investigator identifies an ECG finding that is an adverse event and related to the 
investigational product. Subjects should be in the supine position and the ECG should be 
performed after the subject has rested for at least 5 minutes.   
6.4.2.6  
Physical Examination  
  
The complete physical examination will include appearance, eyes, ears, nose, head, 
throat, neck, lungs, heart, abdomen, extremities, skin, and musculoskeletal system and 
will be performed at the Screening, Cycle 1 Day 1, and End of Study visits. Symptom 
directed physical examinations will be conducted on all subsequent study visits.   
Height will be recorded at Screening only and weight measurements using a medical 
scale will be recorded at each study visit.   
6.4.2.7  
Laboratory Parameters  
  
Safety laboratory assessments will be performed by local laboratories. Screening 
laboratory results may be used for Cycle 1 Day 1 (C1D1) if conducted within 3-7 days.   
  
The laboratory evaluations will include, but are not limited to:   
• 
Hematology/CBC including hemoglobin, hematocrit, platelet count, white blood 
cell (WBC) count, and absolute differential count.   
• 
Peripheral blood lymphocytes subsets; this may include percent of B cells, T cells, 
NK cell, T-Helper cells, T cytotoxic (killer) cells, T reg (suppressor) cells and 
macrophages.   
• 
Serum chemistry: sodium, potassium, chloride, blood urea nitrogen (BUN), 
creatinine, total bilirubin, albumin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, lactate dehydrogenase (LDH), 
sodium, potassium, chloride, bicarbonate, glucose, calcium, magnesium, 
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. Lipase will also 
be measured in patients experiencing diarrhea.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 29 of 46  
• 
Coagulation assessment, including: prothrombin time (PT), and activated partial 
thromboplastin time (aPTT).   
• 
Serology: HBsAg, HCV RNA (qualitative) and HIV.   
• 
Urinalysis (dipstick): pH, glucose, ketones, protein, specific gravity, bilirubin and 
evidence of infection; microscopic examination will be done when findings are 
abnormal.   
• 
Urinalysis (dipstick): pH, glucose, ketones, protein, specific gravity, bilirubin and 
evidence of infection; microscopic examination will be done when findings are 
abnormal.  
• 
Other safety labs: HbA1c, thyroid panel, triglycerides, and prostate specific 
antigen.  
  
6.4.2.8  
Other Safety Variables  
Women of childbearing potential will have a urine or serum pregnancy test every cycle.   
6.4.3  
Description of Pharmacokinetic Variables  
Blood samples for population pharmacokinetics will be collected as detailed in the 
schedule of activities. The date, time, and scheduled time point of the collection, along 
with a reason if the sample is not collected, will be recorded on the eCRF.  
6.5  
Data Quality Assurance  
Report summaries will be generated using validated Base SAS  software, version 9.4 or 
higher, on a PC or server-based platform. Additional validated software may be used to 
generate analyses, as needed.   
All SAS programs that create outputs or supporting analysis datasets will be validated by 
a second statistical programmer or biostatistician. At a minimum, validation of programs 
will consist of a review of the program log, review of output or dataset format and 
structure, and independent confirmatory programming to verify output results or dataset 
content. Additionally, all outputs will undergo a review by a senior level team member 
before finalization.  
The content of the source data will be reviewed on an ongoing basis by project statistical 
programmers and statisticians. Data will be checked for missing values, invalid records, 
and extreme outliers through defensive programming applications, analysis-based edit 
checks, and other programmatic testing procedures. All findings will be forwarded to the 
project data manager for appropriate action and resolution.   


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 30 of 46  
7 STATISTICAL METHODS  
7.1  
General Methodology  
Data will be analyzed by Precision for Medicine biostatistics personnel. Statistical 
analyses will be reported with tables, figures, and listings, presented in rich text format, 
and using recommended ICH numbering. Output specifications for all tables, figures, and 
listings will be in conformance with guidelines specified by the ICH in Appendix 7 of the 
Electronic Common Technical Document Specification (Apr 2003).   
7.1.1  
Reporting Conventions  
Tables and figures will be summarized by dose cohort. All tables (including efficacy) will 
also include a column for all subjects combined. In general, all collected data and any 
derived data will be presented in subject data listings, for all enrolled subjects. Listings 
will be ordered by dose cohort, site (part of subject number), subject number and 
assessment or event date.   
In general, continuous variables will be summarized to indicate the study population 
sample size (N), number of subjects with available data (n), mean, SD, median, 25th (Q1) 
and 75th (Q3) quartiles, minimum, and maximum values, unless otherwise specified. 
Categorical variables will be summarized by the population size (N), number of subjects 
with available data (n), number of subjects in each category, and the percentage of 
subjects in each category. Unless otherwise noted, the denominator to determine the 
percentage of subjects in each category will be based on the number of subjects with 
available data. Select ordinal data may be summarized using both descriptive statistics 
and counts and percentages of subjects in each category, as appropriate.  
Non-zero percentages will be rounded to one decimal place. Rounding conventions for 
presentation of summary statistics will be based on the precision of the variable of 
summarization, as it is collected in its rawest form (i.e., on the electronic case report form 
[eCRF] or as provided within an external file) and are outlined as follows:  
• 
The mean and median will be rounded to one more decimal place than the 
precision of the variable of summarization;  
• 
Measures of variability (e.g., SD, SE) will be rounded to two more decimal places 
than the precision of the variable of summarization; and  
• 
Minimum and maximum values will be presented using the same precision as the 
variable of summarization.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 31 of 46  
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.   
7.1.2  
Summarization by Visit  
Data summarized by study visit will be based on the nominal, scheduled visit label as 
reported on the eCRF.   
Data collected at unscheduled visits will not be included in by-visit summaries, but will 
be considered when endpoint derivations potentially include multiple visits (e.g., 
determination of baseline value, determination of worst post-baseline value, etc.). All data 
will be included in subject listings.  
7.1.3  
Baseline Value  
For analyses listed in this SAP, the baseline value is defined as the last measurement 
reported prior to the first infusion of investigational product, unless otherwise noted. 
Assessments done at the C1D1 visit are performed pre-infusion unless otherwise noted. 
In cases where there is more than one pre-infusion value, the most recent pre-infusion 
value will be determined to be the baseline.   
7.1.4  
Data Handling Rules  
Unless otherwise noted, values reported as greater than or less than some quantifiable 
limit (eg, “< 1.0”) will be summarized with the sign suppressed in summary tables and 
figures, using the numeric value reported. Data will display on subject listings to include 
the sign.  
7.1.5  
Standard Calculations  
Where appropriate, the calculated study day of each assessment or event will be presented 
with the assessment or event date on subject data listings, where study day will be 
determined as:  
• 
The assessment/event date minus the date of first infusion, if the assessment/event 
date is prior to the date of first infusion; and  
• 
The assessment/event date minus the date of first infusion, plus one, if the 
assessment/event date is on or after the date of first infusion.  
Other variables requiring calculations will be derived using the following formulas:  
• 
Days: A duration between two dates expressed in days will be calculated as 
follows:  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 32 of 46  
o Later date – earlier date + 1  
• 
Months: A duration expressed in months will be calculated by dividing the 
duration in days by (365.25 / 12) or 30.4375;  
• 
Years: A duration expressed in years will be calculated by dividing the duration 
in days by 365.25;  
• 
Change from Baseline: Change from baseline will be calculated as the post-
baseline value minus the baseline value;  
• 
Percentage Change from Baseline: Percentage change from baseline will be 
calculated as the change from baseline divided by the baseline value, multiplied 
by 100.  
7.2  
Analysis Populations  
The analysis sets are defined as follows:   
  
• 
Safety analysis set: Includes all subjects who receive at least one infusion of 
investigational product, including partial infusions.   
• 
Efficacy Evaluable analysis set: Includes all subjects who receive at least one 
complete infusion of investigational product, have measurable disease at baseline 
per RECIST v1.1 or modified MDA criteria for bone-exclusive disease and have 
at least one post-baseline on-study assessment of tumor response (based on local, 
Investigator read data). This population will be used for the analysis of efficacy  
data based on local read data and efficacy data which is not dependent on the 
reader (i.e. overall survival). Baseline summaries will also use this population.  
• 
Efficacy Evaluable analysis set (Central): Includes all subjects who receive at 
least one complete infusion of investigational product, have measurable disease at 
baseline per RECIST v1.1 or modified MDA criteria for bone-exclusive disease 
and have at least one post-baseline on-study assessment of tumor response (based 
on central read data). This population will be used for the analysis of efficacy data 
based on central read data only.  
• 
Per-Protocol (PP) analysis set: Includes all efficacy evaluable subjects who have 
no major protocol deviations as defined by the Sponsor prior to database lock.   


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 33 of 46  
7.3  
Study Subjects  
7.3.1  
Disposition of Subjects  
Subject disposition will be summarized for all subjects by dose cohort and over all 
subjects combined. Summaries will include the number and percentage of subjects who 
signed informed consent, who were enrolled, in each analysis set, as well as 
discontinuation of the treatment and early termination of the study by the primary reason 
for discontinuation.   
Time on treatment and time on study will be summarized. Time on treatment is defined as 
(date of last dose – date of first dose + 1)/30.4375. Time on study is defined as (date of 
last contact – date of first dose + 1)/30.4375.  
The number of screen failed subjects will also be presented as well as the reason for their 
screen failure based on which inclusion/exclusion criteria were not met.  
7.3.2  
Protocol Deviations  
Deviations from the protocol and relevant details will be tracked throughout the study and 
summarized as part of the clinical study report. Major protocol deviations will be defined 
prior to data base lock and be summarized with the number and percentage of subjects in 
each category. Deviations will also be given in a by-subject data listing.   
7.4  
Demographic and Other Baseline Characteristics  
7.4.1  
Demographics  
Demographic variables including age, age group (<65 years, ≥ 65 years), sex, ethnicity 
and race, will be summarized by dose cohort and over all subjects combined for the 
Safety, Efficacy Evaluable, and PP analysis sets.   
Age, as collected on the eCRF, will be summarized using descriptive statistics as a 
continuous variable. Sex, ethnicity, race and age group will be summarized with the 
number and percentage of subjects in each parameter category.  
7.4.2  
Baseline Characteristics  
Baseline characteristics, including weight, height, and body mass index (BMI) will be 
summarized by dose cohort and over all subjects in the Safety Efficacy Evaluable, and PP 
analysis sets, using descriptive statistics.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 34 of 46  
7.4.3  
ACC Disease History  
ACC disease history will be summarized by dose cohort and over all subjects in the 
Safety, Efficacy Evaluable and PP analysis sets. The following variables will be included:  
• 
Time since initial diagnosis (months)  
• 
Stage at diagnosis  
• 
Status at screening  
• 
Time since last recurrence/progression (months)  
• 
Site of recurrence/progression  
• 
Bone-only disease  
• 
Bone metastases  
• 
Time since first recurrent or metastatic disease (months).  
Time since initial diagnosis, time since last recurrence/progression and time since first 
recurrent or metastatic disease will be summarized using descriptive statistics. Time will 
be calculated in months relative to the date of the first infusion. The number and 
percentage of subjects will be presented by the following: stage at diagnosis, status at 
screening, site of recurrence/progression, presence of bone-only disease and any bone 
metastases. A subject will be classed as having any bone metastases if the site of 
recurrence/progression includes the word bone, hip, sternum, vertebra, rib, and/or skull 
and/or the site of metastases includes the word bone hip, sternum, vertebra, rib, and /or 
skull.   
Partial initial diagnosis, recurrence/progression and first recurrent or metastatic disease 
dates will be imputed as follows (to allow times to be calculated for all subjects):  
• 
Missing day will be imputed by the 15th of the month;  Missing day and month 
will be imputed by 1st July.  
For the time since first recurrent or metastatic disease, if a subject has Stage IV disease at 
initial diagnosis with a corresponding M stage of M1 and no date of first recurrent or 
metastatic disease diagnosis date is recorded, the date of initial diagnosis will be used as 
the date of first recurrent or metastatic disease (since Stage IV with an M stage of M1 
indicates metastatic disease at initial diagnosis).  
7.4.4  
Prior Cancer Treatment   
Prior cancer treatments including prior cancer therapy, prior cancer surgeries, and prior 
radiation therapy will be summarized by dose cohort and over all subjects in the Safety, 
Efficacy Evaluable and PP analysis sets.  
The following variables will be included:  
• 
Treatment type  
• 
Treatment setting  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 35 of 46  
• 
Number of previous lines of systemic treatment (including neoadjuvant and 
adjuvant)  
• 
Best response  
• 
Duration of response  
• 
Reason for discontinuing therapy  
• 
Prior surgery (including types of surgery)  
• 
Time since last surgery (months)  
• 
Prior radiation  
• 
Time since last radiation therapy (months).  
Number of lines of previous systemic therapy, duration of prior response, time since last 
surgery and time since last radiation treatment will be summarized using descriptive 
statistics. Time will be calculated in months relative to the date of the first infusion. 
Duration of response is collected on the eCRF.   
Partial last surgery/last radiation treatment dates will be imputed as follows:  
• 
Missing day will be imputed by the 1st of the month;  
• 
Missing day and month will be imputed by 1st January.  
7.4.5  
Medical History  
The number and percentage of patients reporting any medical history will be summarized 
by Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 system organ 
class and preferred term.  
7.5  
Efficacy Evaluation  
7.5.1  
Datasets Analyzed  
All efficacy summaries will be based on the Efficacy Evaluable analysis set (central 
version for central read outputs) and will be repeated using the PP analysis set for the 
primary version of each endpoint (the primary version of each endpoint is the first 
version of the endpoint detailed in each of the sections below, i.e. ORR based on 
confirmed – local assessment is the primary version of ORR). OS data will also be 
repeated using the Safety analysis set. A data listing of subjects excluded from any 
analysis set, to include the reason for exclusion, will be presented.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P  age 36 of 46  
All efficacy figures will display AL101 4 mg, AL101 6 mg and the total (combined) 
groups on separate pages.  
7.5.2  
Primary Efficacy Endpoint Analysis Methods  
The primary efficacy endpoint of objective response rate (ORR) will be performed on the 
Efficacy Evaluable analysis set in each cohort separately. There will be no adjustment for 
multiplicity based on the two cohorts, as each cohort is considered an independent trial.  
The estimate of the ORR will be accompanied by a 2-sided 95% exact binomial 
confidence interval (CI) derived using the Clopper-Pearson method.   
The following sensitivity analyses will be conducted:  
• 
The primary analysis will be repeated using the PP analysis set;  
• 
The primary analysis will be repeated using unconfirmed response;  
• 
The primary analysis will be repeated using central read based on confirmed 
response;  
• 
The primary analysis will be repeated using central read based on unconfirmed 
response.  
  
Maximum percentage decrease from baseline in the sum of tumor diameters will be 
displayed in a waterfall plot, by patient and cohort, for all Efficacy Evaluable subjects.   
The estimate of the ORR and associated 2-sided 95% exact binomial CI will also be 
summarized in tabular format and using forest plots for the following subgroups:  
• 
Prior systemic therapy (yes vs no);  
• 
Time since last recurrence (< 6 months vs >= 6 months);  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 37 of 46  
Bone only vs. visceral disease;  
• 
Prior radiation vs. no prior radiation;  
• 
Prior systemic chemotherapy vs no prior systemic chemotherapy.  
In addition, the following will be provided for best overall response only (i.e., no other 
endpoints will have summaries by these subgroups):  
• 
a subgroup analysis of median time on treatment and median time on study by 
best overall response (assessed by the Investigator and irrespective of 
confirmation). In addition to the normal summary statistics, Q1 and Q3 will also 
be displayed on this table.  
Listings showing local and central read responses (target, non-target and overall 
responses for RECIST and overall response by MDA) side by side will be included.   
7.5.3  
Secondary Endpoint Analysis Methods   
All secondary efficacy endpoints will be analyzed in each cohort independently. There 
will be no adjustment for multiplicity among the secondary endpoints. The primary 
analysis of each secondary endpoint will be conducted using the Efficacy Evaluable 
analysis set. Sensitivity analyses will be conducted using alternative analysis sets as 
described in each section below.  
7.5.3.1  
Duration of Response   
The Kaplan-Meier method will be used to analyze DOR. The Kaplan-Meier curves will 
be plotted. Counts and percentages for number of subjects who experienced the event of 
interest and those who are censored will be presented along with minimum and maximum 
duration in months. The median, 25th and 75th percentiles will be estimated and their 
corresponding Brookmeyer-Crowley 95% CIs using the Kaplan-Meier estimates. 
Landmark estimates will be provided for 2, 4, 6 and 8 months after start of investigational 
product.   
The following sensitivity analyses will be conducted:  
• 
The DOR analysis will be repeated using the PP analysis set;  
• 
The DOR analysis will be repeated using unconfirmed response;  
• 
The DOR analysis will be repeated using central read based on confirmed 
response;  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 38 of 46  
The DOR analysis will be repeated using central read based on unconfirmed 
response.  
Subgroup analyses will not be performed for DOR due to the small number of 
responders.  
DOR will be displayed graphically by patient and cohort using swimmer plots.  
7.5.3.2  
Progression Free Survival   
PFS will be summarized similarly to DOR using the Kaplan-Meier method and estimates 
will be presented along with Brookmeyer-Crowley 95% CIs. Appropriate landmark 
estimates will also be included.   
The following sensitivity analyses will be conducted:  
• 
The PFS analysis will be repeated using the PP analysis set;  
• 
The PFS analysis will be repeated using central read;  
• 
The PFS analysis will be repeated using the subset of subjects with a BOR of PR 
(BOR will be based on the Investigator results irrespective of confirmation; PFS 
will be based on the Investigator results).  
Subgroup analyses will also be performed based on the main subgroups outlined above 
for ORR. Kaplan-Meier curves will be plotted for each subgroup.  
7.5.3.3  
Overall Survival  
OS will be summarized similarly to DOR using the Kaplan-Meier method and estimates 
will be presented along with Brookmeyer-Crowley 95% CIs. Appropriate landmark 
estimates will also be included.   
The following sensitivity analyses will be conducted:  
• 
The OS analysis will be repeated using the PP analysis set;  
• 
The OS analysis will be repeated using the Safety analysis set;  
• 
The OS analysis will be repeated using the subset of subjects with a BOR of PR 
(BOR will be based on the Investigator results irrespective of confirmation).  
Additional analyses of OS will be conducted using the same methods as outlined above, 
with the following changes to the definition of OS:  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 39 of 46  
Calculated using date of first recurrent or metastatic disease instead of date of first 
infusion as time 0 (the same rules as detailed in Section 7.4.3 will be used to 
impute partial dates and in some cases, missing, dates);    
• 
Calculated using date of initial ACC diagnosis instead of date of first infusion as 
time 0 (the same rules as detailed in Section 7.4.3 will be used to impute partial 
dates).  
Subgroup analyses will also be performed based on the main subgroups outlined above 
for ORR. Kaplan-Meier curves will be plotted for each subgroup.  
7.5.3.4  
Time to Response   
TTR will be summarized similarly to DOR using the Kaplan-Meier method and estimates 
will be presented along with Brookmeyer-Crowley 95% CIs. Appropriate landmark 
estimates will also be included.   
The following sensitivity analyses will be conducted:  
• 
The TTR analysis will be repeated using the PP analysis set;  
• 
The TTR analysis will be repeated using unconfirmed response;  
• 
The TTR analysis will be repeated using central read based on confirmed 
response;  
• 
The TTR analysis will be repeated using central read based on unconfirmed 
response.  
Subgroup analyses will also be performed based on the main subgroups outlined above 
for ORR. Kaplan-Meier curves will be plotted for each subgroup.  
7.5.3.5  
Disease Control Rate  
DCR will be summarized similarly to ORR.   
The following sensitivity analyses will be conducted:  
• 
The DCR analysis will be repeated using the PP analysis set;  
• 
The DCR analysis will be repeated using unconfirmed response;  
• 
The DCR analysis will be repeated using central read based on confirmed 
response;  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 40 of 46  
The DCR analysis will be repeated using central read based on unconfirmed 
response.  
Subgroup analyses will also be performed based on the main subgroups outlined above 
for ORR. The results will be displayed graphically in forest plots.  
7.5.3.6  
Change in EORTC QLQ-C30  
EORTC QLQ-C30 functional scales (physical, role, emotional, cognitive, and social), 
symptom scales (fatigue, pain, and nausea and vomiting), global health status / QoL 
scale, and single items assessing additional symptoms commonly reported by cancer 
patients (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea and perceived 
financial impact of the disease) will summarized using descriptive statistics (mean, SD, 
median, 25th (Q1) and 75th (Q3) quartiles, and minimum/maximum values). Descriptive 
statistics will be calculated for observed values and change from baseline at each visit 
where the EORTC QLQ-C30 is assessed.   
7.5.4  
Statistical/Analytical Issues  
7.5.4.1  Adjustments for Covariates No 
covariate adjustments are planned.   
7.5.4.2  
Handling of Dropouts or Missing Data  
The primary analysis of ORR will consider a subject with no evaluable response data to 
be a non-responder.  
Every effort will be made to determine each subject’s progression and survival 
information. However, subjects may withdraw their consent at any time from further 
participation in the study. Subjects may withdraw consent from treatment, survival 
follow-up, or both.   
In analyses presented over time by visit, no imputations will be performed on missing 
data. All analyses will be based on observed data only. The effective sample sizes at each 
assessment visit will be based on the total number of subjects with non-missing data for 
the parameter of interest at that visit.  
Unless otherwise specified, the following general imputation rules will be used for 
missing date in the assessment of an event:  
If all parts of the date are missing, the date will not be imputed. In the case where only 
the start day of an event is missing, it will be replaced by the start day of study treatment 


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 41 of 46  
if the event occurs in the same month and year. Otherwise, it will be replaced by the first 
of the month. If the stop day is missing and the month is equal to the month of the last 
date of study treatment, the stop day of the event will be replaced by the stop day of study  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 42 of 46  
treatment. Otherwise, the last day of the month will be used to replace the missing stop 
day.  
If both the start day and month of an event are missing, the start day and month will be 
replaced by the start day and month of study treatment if the event and the start of the 
treatment occur in the same year; otherwise, it will be replaced by 1st of January. All 
imputed dates will have to be prior to the dates of withdrawal of consent, lost to 
followup, and death.   
7.5.4.3  
Interim Analyses and Data Monitoring  
Throughout the study, a DMC will monitor safety parameters at regular intervals 
(approximately quarterly) after at least 3 subjects have been treated for at least 1 cycle. 
There was no formal interim analysis undertaken. Multicenter Studies  
This is a multicenter study. Sites in North America, Europe, and Canada are expected to 
participate. All data collected from all study centers will be pooled for data analysis.   
7.5.4.4  
Multiple Comparisons/Multiplicity  
No adjustments for multiple comparisons will be made. A single primary endpoint has 
been identified and each cohort is viewed as a separate study. No adjustment among 
secondary endpoints will be made as this study is exploratory.  
7.5.4.5  
Use of an “Efficacy Subset” of Subjects  
The efficacy analysis will be performed on the Efficacy Evaluable analysis set since this 
population is the subset of the Safety analysis set who have measurable disease at 
baseline and have at least one post-baseline on-study assessment of tumor response.  
The PP analysis set will be utilized as a sensitivity analysis. The PP analysis set will 
exclude subjects with major protocol violations as determined by the Sponsor prior to 
database lock.  
7.5.4.6  
Active-Control Studies Intended to Show Equivalence  
This study does not include an active-control product and is not intended to demonstrate 
equivalence between any two drug products.  
7.5.4.7  
Examination of Subgroups  
The primary and secondary efficacy endpoints (excluding the QoL data) will be 
summarized by various subgroups of interest. The subgroups are defined in Section 7.5.2.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 43 of 46  
Additional subgroup analyses may be performed post-hoc, as appropriate.  
7.6  
Population Pharmacokinetic Analysis  
Population Pharmacokinetic analysis will be summarized in the “Pharmacokinetic 
Modeling and Simulation Analysis Plan for AL101 and AL101 Active Metabolite” and is 
outside the scope of this SAP.   
As a part of this SAP PK sample collection data will be presented in a by subject data 
listing only.   
7.7  
Exploratory Biomarker Analysis  
Exploratory analysis of the correlation between N1CDI staining and Notch1 mutations 
and the correlation of Notch mutations and associated genes with response or resistance 
to investigational product will be summarized in the “Biomarker Statistical Analysis 
Plan.”  and is outside the scope of this SAP  
Next Generation Sequencing assay results at Screening will be presented in a by subject 
data listing. Tumor biopsy and blood biomarker sample collection information will also 
be presented in a by subject data listing only.   
7.8  
Safety Evaluation  
Safety analysis will be carried out for the Safety analysis set, to include all subjects who 
receive at least one infusion of investigational product, including partial infusions. 
Subjects who do not complete the study, for whatever reason, will have all available data 
up until the time of termination included in the analysis. Safety summaries will be 
presented by dose cohort and with all subjects combined. For safety analysis presented by 
study visit, the baseline value will be defined as the last value reported prior to first 
investigational product infusion.   
7.8.1  
Extent of Exposure and Treatment Compliance  
Extent of exposure to study treatment will be summarized by dose cohort and over all 
subjects combined for the Safety analysis set.  
The number of infusions attempted, total amount AL101 received (mg) and number of 
cycles initiated (overall and by subject) will be summarized using descriptive statistics. 
The number of cycles initiated will also be summarized by the number and percentage of 
subjects with each number of cycles initiated. The total number of AL101 administrations 
received as planned and not received as planned will be summarized. The number and 
percentage of subjects with each reason for infusions not being administered as planned 


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 44 of 46  
will also be displayed. The number and percentage of subjects with a planned dose 
reduction from 6 mg to 4 mg or from 4 mg to 2.4 mg will be presented.  
7.8.2  
Adverse Events   
TEAEs will be summarized by dose cohort and over all subjects combined for the Safety 
analysis set.  
Summaries that are displayed by system organ class and preferred terms will be ordered 
by descending incidence of system organ class and preferred term within each system 
organ class. Summaries displayed by preferred term only will be ordered by descending 
incidence of preferred term.   
Summaries of the following types will be presented:  
• 
Overall summary of number of unique TEAEs, treatment-emergent serious 
adverse events (SAEs) and subject incidence of TEAEs meeting various criteria;  
• 
Subject incidence of TEAEs by MedDRA system organ class and preferred term;  
• 
Subject incidence of TEAEs by MedDRA preferred term;  
• 
Subject incidence of TEAEs by severity grade, MedDRA system organ class, and 
preferred term;  
• 
Subject incidence of TEAEs related to investigational product, MedDRA system 
organ class, and preferred term;   
• 
Subject incidence of TEAEs related to investigational product by severity grade,  
MedDRA system organ class and preferred term;   
• 
Subject incidence of TEAEs Grade ≥ 3 by MedDRA system organ class and 
preferred term;   
• 
Subject incidence of TEAEs Grade ≥ 3 and related to investigational product by 
MedDRA system organ class and preferred term;   
• 
Subject incidence of SAEs by MedDRA system organ class and preferred term.  
• 
Subject incidence of SAEs related to investigational product by MedDRA system 
organ class and preferred term.  
• 
Subject incidence of AESIs by MedDRA system organ class and preferred term.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 45 of 46  
• 
Subject incidence of AESIs related to investigational product and MedDRA 
system organ class and preferred term.  
• 
Subject incidence of TEAEs leading to death by MedDRA system organ class and 
preferred term.  
• 
Subject incidence of TEAEs leading to drug discontinuation by MedDRA system 
organ class and preferred term.  
At each level of summarization (eg, any AE, system organ class, and preferred term), 
subjects experiencing more than one TEAE will be counted only once. In the summary of 
TEAEs by severity grade, subjects will be counted once at the highest severity reported at 
each level of summarization; in the summary of TEAEs by relationship, subjects will be 
counted once at the closest relationship to investigational product.   
AEs reported with a causality term of “Certain,” “Probable/Likely,” “Possible,” 
“Conditional/Unclassified” and “Unassessable/Unclassifiable” will be considered to be 
related to the investigational product and those reported as “Unlikely” will be considered 
not related.   
Adverse event data will be presented in data listings by subject and event.   
7.8.2.1  
Adverse Events of Special Interest  
  
AESIs will be summarized by subject incidence by MedDRA system organ class and 
preferred term.  
AESIs will be presented in a separate data listing.  
7.8.3  
Deaths, Other Serious Adverse Events, and Other Significant Adverse  
Events  
All deaths during the study, including the long-term follow-up period, will be listed by 
subject, to include the primary cause of death (where applicable). The day of death 
relative to date of last dose will also be presented. Serious AEs and other significant AEs, 
including AEs and AESIs that led to withdrawal, interruption, or dose reduction of the 
investigational product, will be provided in separate subject data listings.  
7.8.4  
Clinical Laboratory Evaluation  
Clinical laboratory measurements, including serum chemistry, hematology and 
coagulation, will be summarized for all subjects in the Safety analysis set by dose cohort 
and over all subjects combined.   


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 46 of 46  
All descriptive summaries of laboratory results will be based on data analyzed by the 
local laboratory and presented in Système International (SI) units, as suggested by the 
Center for Biologics Evaluation and Research and the Center for Drug Evaluation and  
Research Position on Use of SI Units for Lab Tests (Oct 2013). All data will be included 
in by-subject data listings. Laboratory measurements identified as abnormal (ie, outside 
the normal range) will also be listed separately by subject, laboratory test, and unit.  
Descriptive statistics will be presented for observed values and changes from baseline at 
each visit where parameters were scheduled to be collected per the clinical study 
protocol.   
Where applicable, hematology, chemistry and coagulation results for select parameters 
will be assigned a toxicity grade based on the U.S. Department of Health and Human 
Services Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (Nov 
2017). Five-by-five contingency tables will be presented for lab tests where toxicity 
grading can be applied to summarize the shift from the baseline grade to the worst 
postbaseline grade. Grades will be presented as none (Grade 0), mild (Grade 1), moderate 
(Grade 2), severe (Grade 3), or life-threatening (Grade 4). Death related to AE (ie, Grade 
5) cannot be determined with available laboratory-based data collection and, thus, will 
not be summarized as a category. Summary results will include the count and percentage 
of subjects within each shift category. Percentages will be based on the number of 
subjects with baseline and at least 1 post baseline assessment.  
Hy’s Law will be used to assess subjects for drug induced liver injury. The criteria for  
Hy’s Law is defined as having an ALT or AST result >3x ULN and Total Bilirubin >2x 
ULN and ALP < 2x ULN. The frequency and percentage of subjects meeting criteria will 
be summarized for each visit.  
Urinalysis parameters will be presented in by-subject data listings only.   
7.8.5  
Vital Signs, Physical Findings, and Other Observations Related to Safety  
7.8.5.1  
Vital Signs  
Vital signs (including heart rate, respiratory rate, temperature, and blood pressure) will be 
summarized by dose cohort and over all subjects combined for the Safety analysis set. 
Descriptive statistics will be presented for results and change from baseline at each visit 
where parameters were scheduled to be collected.   
BMI will be derived as weight (kg) / [height (m)]2, based on the collected weight at each 
visit and height collected at Screening. Descriptive statistics will be presented for results 
and change from baseline at each visit where parameters were scheduled to be collected.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 47 of 46  
7.8.5.2  
12-Lead Electrocardiogram  
Twelve-Lead ECG interval parameters of heart rate, PR interval, RR Interval, QRS 
duration, QT interval, QTcF, and QTcB will be summarized by dose cohort and over all 
subjects combined for the Safety analysis set. Descriptive statistics will be presented for 
observed values and changes from baseline at each visit where parameters were 
scheduled to be collected.  
Twelve-lead ECG will be classified by the investigator as “normal,” “abnormal, not 
clinically significant,” “abnormal, clinically significant.” Three-by-three contingency 
tables will be presented to summarize the shift from the baseline category to the worst 
post-baseline value. Summary results will include the count and percentage of subjects 
within each shift category that had evaluable ECG results. This analysis will be repeated 
for the central interpretation of the ECGs (central read ECGs do not have clinical 
significance assigned so only normal/abnormal will be displayed).  
Prolonged QTcF and QTcB intervals will be summarized as QTc measurements (msec) 
that are > 450, > 480, and > 500 at each visit where ECG is routinely collected per the 
clinical study protocol. Change from baseline categories will also be summarized for 
measurements that represent a change > 30 or > 60 relative to the baseline value.   
7.8.5.3  
ECOG Performance Status  
ECOG exams are to be performed at all study visits.   
ECOG will be summarized by dose cohort and over all subjects combined for the Safety 
analysis set. The shift from the baseline ECOG performance score to the worst 
postbaseline score will be summarized with the number and percentage of subjects in 
each shift category for the Safety analysis set (by dose cohort and over all subjects 
combined). ECOG scores will also be presented in data listings by subject and 
assessment date.  
7.8.5.4  
Physical Examination  
Results of the physical examination will be presented in subject data listings by subject, 
study visit, and body system.  
7.8.5.5  
Prior and Concomitant Medications  
Medications will be coded using the World Health Organization (WHO Drug B3) 
dictionary. Medications entered on the eCRF will be mapped to Anatomic Therapeutic 
Chemical (ATC) drug class (level 4) and drug name.   


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 48 of 46  
Prior and concomitant medications will be summarized separately and the study phase of 
each medication will be determined programmatically based on medication start and end 
dates. A prior medication is defined as any medication administered prior to the date of 
the first infusion of investigational product. A concomitant medication is defined as any 
medication administered on or after the date of the first infusion of investigational 
product. A medication may be defined as both prior and concomitant. If it cannot be 
determined whether a medication was received prior to the start of investigational product 
dosing due to partial or missing medication start and/or end dates, it will be considered a 
prior medication. Likewise, if it cannot be determined whether a medication was received 
after the start of investigational product dosing, it will be considered concomitant.  
For the summary of both prior medications and concomitant medications, the number and 
percentage of subjects receiving any medication will be summarized for all subjects in 
the Safety analysis set, as will the number and percentage receiving any medication by 
ATC drug class and generic drug name. Subjects reporting use of more than one 
medication at each level of summarization (any medication received, ATC class, and 
generic drug name) will be counted only once. ATC class terms will be displayed by 
descending order of incidence, as will generic drug names within each ATC class. The 
study phase during which each medication was received (eg, prior, concomitant, or both) 
will be presented on the listing of prior and concomitant medications.  
7.9  
Determination of Sample Size  
The study was initiated as a Simon’s two-stage optimal design. The study passed the 
futility analysis in Stage 1 of the Simon two-stage design and is currently continuing to 
enroll subjects. While the data on Cohort 1 (4 mg QW) is maturing, the study will enroll 
up to a maximum of 45 subjects in Cohort 1 and in parallel will be expanded with the 
addition of Cohort 2 (6 mg QW). The study will continue enrolling a total of 42 subjects 
in Cohort 2, 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. An 
additional interim look may be undertaken at 50% of the total information fraction (21 
subjects) for Cohort 2.  
The updated design, a 2-look Group Sequential design with stopping for futility based on 
Pocock beta-spending function takes the first look after 21 subjects and has the following 
operating characteristics:   
Total n  
Stages  
1st look n  
2nd look n  r1 futility  
r2 futility  
Power  
42  
2  
21  
42  
2  
6  
89.4  
The expansion of Cohort 1 to a maximum of 45 subjects and Cohort 2 to a maximum of 
42 subjects will provide at least 80% power the testing the hypothesis of achieving an 
increase of the response rate from 8% to 25% using a type I error of 5%.  


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 49 of 46  
The futility analysis for Cohort 1 was passed; the futility analysis for Cohort 2 was not 
conducted.  
7.10  Changes in the Conduct of the Study or Planned Analyses  
Disease control rate and time to response were added as secondary efficacy endpoints to 
further explore the clinical activity.   
There were no other changes to the study conduct or planned analyses identified within 
the development of this SAP, relative to the descriptions provided within the clinical 
study protocol.   
  
  
 


  
  
Ayala Pharmaceuticals, Inc.  
Statistical Analysis Plan  
AL-ACC-101  
  
Version 2.0; 18 October 2022  
  
FORM BS-003-A                                       Confidential   
V01.1  
SAP Template                                     Precision for Medicine                                                     P age 50 of 46  
8 REFERENCE LIST  
  
[1] 
Eisenhauer, E. A., P. Therasse, et al. (2009). "New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1)." European journal of cancer 45(2): 
228247.   
  
[2] 
Simon, R. (1989). "Optimal two-stage designs for phase II clinical trials." 
Controlled clinical trials 10(1): 1-10.   
  


 
 
Gary Gordon 
gary.g@ayalapharma.com 
Chief Medical Officer 
Ayala Pharmaceuticals 
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