A Phase I Open-label Multicentre Dose-escalation Study of Subcutaneous ALM201 in Patients With Advanced Ovarian Cancer and Other Solid Tumours
Phase: PHASE1
Conditions: Solid Tumors, Ovarian Cancer
Sponsor: Almac Discovery

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CLINICAL STUDY PROTOCOL SYNOPSIS
A phase I open-label multicentre dose-escalation study of subcutaneous 
ALM201 in patients with advanced ovarian cancer  
and other solid tumours 
Study Protocol: 
ALM201/0001 
Study Drug(s): 
ALM201 
Version No:  
F2.0 
Version Date:  
24 SEP 14 
2014-001175-31 
EudraCT No:  
NCT No: 
Sponsor: 
Almac Discovery 
Almac House 
20 Seagoe Industrial Estate 
Craigavon  
BT63 5QD 
UK 
Phone: 
+44 2838332200 
Fax: 
+44 2838332299 
03427073

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PROTOCOL SYNOPSIS 
Protocol No:  
ALM201/0001 
Study Title:  
A phase I open-label multicentre dose-escalation study of subcutaneous ALM201 in patients with 
advanced ovarian cancer and other solid tumours. 
Investigational Product: 
ALM201 
Phase of Development: 
1 
No of Sites: 
 
For dose escalation (Part 1): 3 UK sites 
For further assessment of the Maximum Tolerated Dose (MTD), Maximum Feasible Dose (MFD) 
and/or Biologically Active Dose (BAD) in Part 2: up to 5 additional UK sites may be added in order 
to ensure there is an acceptable enrolment rate. 
No of Patients: 
The final sample size will depend on the number of Dose Limiting Toxicities (DLTs) observed at 
each dose level and any Cohort Review Committee (CRC) decision to assess an alternative treatment 
schedule in Part 1, plus the number of enrichment cohorts assessed at the MTD, MFD and/or BAD in 
Part 2.   
Up to 36 evaluable patients would be anticipated for Part 1 based on a conservative estimate of 
enrolling a maximum of 36 patients across 6 dose escalation cohorts.  Up to an additional 12 patients 
may also be enrolled to Part 1 for the assessment of alternative dose schedule(s). 
No more than 36 evaluable patients will be enrolled for Part 2.  This upper limit is based on an 
estimate of up to 12 patients being evaluated at 3 dose levels of interest.   
Study Objectives and Endpoints: 
The primary objectives of this study are to characterize the safety and tolerability of ALM201 and to 
identify a recommended phase 2 dose and schedule of administration of ALM201 in patients with 
advanced ovarian cancer. 

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Objective 
Endpoint(s) (Assessment) 
Primary: 

To characterise the safety and tolerability of
ALM201 (Parts 1 and 2)

To identify a recommended phase 2 dose and
schedule of ALM201 (Part 2 only)

Ongoing evaluation of AEs during
treatment and follow up; evaluation of
DLT during Cycle 1 (Part 1 only)

Safety, PK, PD and tumour response
assessments
Secondary: 

To establish the pharmacokinetic profile of
ALM201

Assessment of pharmacokinetic variables
(including Cmax, Cmin, AUC)

To assess anti-tumour activity

To assess anti-tumour activity in a
biomarker-enriched group of patients with
advanced ovarian cancer (Part 2 only)

Tumour response assessment by RECIST
1.1(Eisenhauer et al, 2009i) and/or other
relevant response assessments for tumour
types enrolled

Tumour response assessment by RECIST
1.1(Eisenhauer et al, 2009i)
Exploratory: 

To assess relevant tumour biomarkers and
the pharmacodynamic activity of ALM201

Assessment of relevant tumour biomarkers
and markers of ALM201 activity
o
in archival and/or fresh tumour biopsy
material e.g. CD44, FKBPL, CD31,
pFAK, pHer2, ITGA5, CA-125, ER,
PR, angiogenesis signature and other
relevant or exploratory biomarkers as
appropriate for tumour type
o
in blood e.g. RASSF1 methylation,
and other relevant or exploratory
biomarkers appropriate for tumour
type
o
in ascites (Part 2 only) e.g. stem cell
count, and other relevant or
exploratory biomarkers appropriate
for ovarian cancer
Study Design: 
This is a Phase 1, open-label, dose escalation study of the safety, tolerability, and pharmacokinetics 
(PK) of ALM201. The study will commence by enrolling patients with advanced solid tumours in 
whom treatment with an anti-angiogenic agent is appropriate.  Eligible participants will be enrolled 
in sequential cohorts treated with ALM201, given as a sub-cutaneous (SC) injection while being 
monitored for safety and DLTs.    

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Dose levels will not be weight-adjusted and the starting dose for the study will be 10 mg ALM201 
given on Days 1-5, 8-12 and 15-19 every 21 days i.e. weekday dosing.  Dose increments will not 
exceed 100% and will be guided by safety data observed during Cycle 1, as well as on-going 
assessment of safety beyond Cycle 1 in earlier cohorts, plus PK and PD data as available.  Every new 
dose cohort will be evaluated for the occurrence of a DLT during Cycle 1 of treatment (Section 
4.2.1). 
Accelerated enrolment followed by a 3+3 design 
Part 1 of the study will commence with an accelerated dose escalation schedule and enrol 1 patient 
into a cohort with follow up for adverse events (AEs) and DLT during Cycle 1. The CRC will meet 
as soon as possible once the final study visit in Cycle 1 has taken place in each cohort to review 
patient safety data to the end of Cycle 1.  Where there are no safety concerns, a 100% dose escalation 
step will be permitted for the next cohort.  Where the CRC suspects that drug-related events have 
occurred that could progress to DLT upon further dose escalation e.g. clinically significant NCI 
(National Cancer Institute) CTCAE (Common Terminology Criteria for Adverse Events) Grade 2 
events considered to be related to ALM201, they will confirm that future cohorts must enrol at least 
3 patients in order to more thoroughly evaluate potential drug-related adverse events.  The CRC may 
also advise that the current dose level under evaluation be expanded to 3 patients prior to further dose 
escalation in order to help inform the next dose escalation step.  Dose escalation of 3-patient cohorts 
will proceed according to the scheme presented in Section 4.2.  Note that there will always be stagger 
of at least 1 week between dosing the first and subsequent patients in a new dose cohort.  The CRC 
may request there be a further or prolonged stagger introduced during the trial, depending on the 
nature of adverse events observed to date. 
Dose Limiting Toxicity 
The CRC will agree on the next appropriate dose escalation step for each cohort primarily based on 
DLT evaluation during Cycle 1 of the current cohort.  Only events occurring during the first cycle of 
treatment will be considered for DLT determination; however, there will be on-going evaluation of 
AEs in subsequent treatment cycles during the cohort review process. Clinically significant events 
thought to be potentially related to ALM201, or trends in adverse events seen in subsequent cycles 
will be taken into account when considering future dose escalation steps and dose administration 
schedules.   
Upon occurrence of the first DLT in any cohort, additional patients will be added to that cohort so 
that up to a total of 6 can be evaluated.  Once expansion to a 6-patient cohort has been recommended 
due to the identification of a DLT, escalation to the next 3-patient cohort will only occur when all 
patients in the expanded cohort have completed their first cycle of ALM201 and no more than 1 DLT 
has occurred.  If 2 or more DLTs occur in an expanded cohort, DLT is established and the next lower 
dose level will be declared the MTD.   
The highest dose where ≤ 1 DLT is seen in 3 or 6 patients will be termed the MTD.  Note that 
intermediate dose levels may be explored below the dose level where ≥2 DLTs were seen, in order to 
identify the maximum dose which may be adequately tolerated.  The CRC may also specify a 
recruitment stagger to be followed during cohort expansion for DLT evaluation depending on the 
nature of the DLT and the considered risk to patients. 

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In the case where an MTD is not established, the maximum feasible single dose which may be 
administered will be dictated by the formulation of ALM201 and the maximum volume for SC 
administration i.e. 3 x 1 mL injections, which will administer a dose of 300 mg ALM201 (Section 6).  
Should this dose be reached without the need to de-escalate due to DLT, it will be termed the MFD.   
Based on the review of PD data in conjunction with on-going safety and PK data, the CRC may also 
identify a BAD for further exploration in Part 2 of the study. 
Safety evaluations will be conducted weekly during each treatment cycle, with DLT assessed during 
Cycle 1 only.  All events and suspected DLTs will be graded according to the CTCAE v4.03. 
A DLT is defined as a Grade 3 or 4 AE that, in the opinion of the CRC, is likely to be related to 
ALM201 and represents a clinically significant hazard to the subject.  Qualifying DLT events must 
be considered to be clinically relevant e.g. in duration, apparent reversibility, required management, 
and upon consideration of the patient’s medical history and/or concomitant medications.  DLT events 
must also be evaluated in terms of what is considered to be an appropriate next escalation step: in the 
case where the CRC agree that an escalation step of approximately 33% or lower is merited, the 
toxicity of concern should be declared a DLT. 
Examples of exceptions that will be considered by the CRC are as follows: 

Grade 3 or 4 laboratory abnormalities, which resolve spontaneously or can be corrected with
appropriate treatment (such as electrolytes) e.g. an event returns to baseline or to Grade 1 or
less prior to the next administration);

Symptomatic adverse events, such as nausea, vomiting and diarrhea, if they can be reduced to
less than Grade 3 with standard supportive measures, such as anti-emetics and anti-
diarrhoeals within 72 hours.
In order to be evaluable for DLT assessment, a patient must have received at least 80% of their 
scheduled doses (e.g. 12 of the 15), unless this lack of compliance is due to ALM201-related 
toxicity.  DLT events must therefore be considered in terms of inability to administer the planned 
Cycle 1 dose administration schedule, and in such cases a dose delay of more than 14 days due to a 
toxicity event considered related to ALM201 will be considered to be a DLT (Section 4.4.1).  
Part 1: Dose Escalation 
In the absence of DLT or suggestion of ALM201-related adverse events which would lead to more 
cautious dose escalation, the following table presents a hypothesised dose escalation plan: 
Cohort 
Escalation Step 
Dose level 
1 (Starting Dose) 
- 
10 mg 
2 
(2X starting dose) 
20 mg 
3 
(4X starting dose) 
40 mg 
4 
(8X starting dose) 
80 mg 
5 
(16X starting dose) 
160 mg 
6 (MFD) 
(30X starting dose) 
300 mg 

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The dose may be doubled in sequential cohorts where the CRC consider it appropriate to do so, 
based on on-going evaluation of DLTs and adverse event data.  Dose escalation decisions will also 
take available PK and pharmacodynamic (PD) data into consideration. 
In the case where a potentially significant toxicity occurs, or a trend in toxicities is seen, considered 
to be related to treatment with ALM201 and potentially a precursor to a clinically significant toxicity 
event, subsequent dose escalation steps will be more conservative and will not exceed 50% of the 
previous dose.  This restriction may be reversed where there is no suggestion of potentially clinical 
significant toxicity in subsequent cohort(s).  In the case where a single DLT event is confirmed in an 
expanded cohort, the next dose escalation step will not exceed 33% of the previous dose.  However, 
where there are no further events seen in the next cohort; the CRC may allow future dose escalation 
steps of up to 50%. 
Note that the CRC may also recommend that an MTD, MFD or BAD be assessed in a cohort of 6 
patients in Part 1 where only 3 patients have received this dose level to date, prior to recommending 
the enrolment of an enrichment cohort to receive this dose level in Part 2.  
Cohort Review Committee 
All dose escalation decisions will be made by a CRC who shall convene to review all available AE, 
PK, PD and relevant patient data (Section 8.1).  Patients in Part 1 will be eligible for DLT evaluation 
if they have received 80% e.g. 12 of their 15 scheduled doses, during Cycle 1.  The CRC will be 
composed of the trial investigators, a patient representative, sponsor representative(s) and the study 
Medical Monitor.  Additional experts may be invited to support the review of the data as required 
e.g. a pharmacokineticist.  The Contract Research Organisation (CRO) responsible for managing and 
monitoring the trial will also support the preparation and conduct of the CRC meetings and may 
attend such meetings.  All data reviewed, CRC discussions and agreed dose escalation 
recommendations will be minuted.  The composition of the CRC and the data review processes to be 
followed by the committee will be fully described in a CRC Charter.   
Based on on-going safety, PK and PD data evaluation, the CRC may also recommend dose 
de-escalation steps or adjustments in the dose administration schedule of ALM201.  Upon review of 
available safety, PK and PD data, the CRC may recommend that an alternative dose administration 
schedule of ALM201 be explored.  Less intense dose administration schedules will be permitted as 
long as the unit dose does not exceed the next permitted escalation step.  Given the starting dose 
administration schedule is week-day dosing i.e. D1-5, D8-12, D15-19, on a 21 day cycle, a more 
dose intense dosing schedule is unlikely.  However, should the CRC consider this reasonable to 
explore, the same dose escalation rules will apply and pharmacokinetic modelling, in conjunction 
with the safety data obtained to date, will be used to inform the appropriate dose level for a more 
dose intense dose schedule. 
Note that the MTD or MFD need not be confirmed for the original dose administration schedule 
prior to the CRC recommending the investigation of an alternative dose administration schedule.  
Multiple dose escalation tracks may be followed if more than one dose schedule is considered 
relevant to explore i.e. the CRC may recommend that the alternative dose administration schedule 

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replaces a schedule or is explored in addition to another schedule, as long as dose escalation rules are 
not exceeded. 
Duration of treatment 
The main study will permit a maximum of 8 three-weekly treatment cycles (or approximately 6 
months of treatment).  Patients who are seen to potentially be benefiting from treatment i.e. patients 
whose disease has not progressed and who have not been withdrawn from therapy due to toxicity, 
will be eligible to continue to receive additional cycles of ALM201 where this is recommended by 
their study physician, subject to availability of ALM201.  Such patients will continue to be followed 
up for compliance, toxicity and continued response (Schedule of Study Assessments).   
Part 2: Enrichment at MTD, MFD and/or BAD 
Once an MTD, MFD and/or BAD has been established for a given dose and schedule in Part 1, Part 
2 may commence.  Part 2 will involve up to an additional 36 patients with advanced ovarian cancer.   
During Part 2 of the study there will be on-going evaluation of safety and the opportunity to obtain 
preliminary anti-tumour activity at each dose level selected in the ovarian cancer population.  The 
only dose adjustments permitted in Part 2 will be dose de-escalations (based on a de-escalation of the 
unit dose or a less frequent administration schedule of the maximum unit dose).  Such decisions will 
be driven by each patient’s tolerability of ALM201.  Where possible, such dose reductions should be 
made by the CRC who can convene on an ad-hoc basis to advise on the appropriate dose adjustment; 
however, the investigator may implement a dose reduction prior to CRC review in the interest of 
patient safety. 
Study Assessments:  
The study will commence with a dosing schedule of ALM201 monotherapy given SC on Days 1-5, 
8-12 and 15-19 in a 3 week cycle.   
Patients will have scheduled site visits on every dosing day of the first cycle, then on Days 1, 8 and 
15 of Cycles 2-4.  From Cycle 5 onwards, they are only required to visit the clinic on Day 1 of each 
cycle.  ALM201 administration can be given at home on all other days.  
Safety assessments will include physical examination, vital signs, biochemistry and haematology 
laboratory screens, plus immunogenicity testing (see Schedule of Study Assessments).  Adverse 
events will also be noted at every clinical visit and recorded at least every week.  For all 
administrations in hospital, the patients must wait for at least 60 minutes from the time of the 
ALM201 injection for observation and repeat vital signs.  These precautions are in case of emergent 
evidence of immunogenicity in Cycle 1, and at other times after the weekend break in dosing.   
Tumour assessment by imaging (computed tomography (CT) scan or magnetic resonance imaging 
(MRI) scan as appropriate for tumour type) will be assessed in all patients at Screening and after 
every 2 cycles of treatment (i.e. every 6 weeks) during Cycles 1–8 (first 24 weeks), and then after 
every 4 cycles of treatment (i.e. every 12 weeks) from Cycle 9 onwards.  Scans may be performed at 
other times as clinically indicated.  
Tumour assessment by informative tumour markers where relevant for tumour type e.g. GCIG 

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criteria for CA125 (Rustin, et al.  2011ii), PSA, CEA or CA19-9, will be assessed in all patients at
Screening and after every 2 cycles of treatment during treatment (i.e. every 6 weeks).  Tumour 
markers may be performed at other times as clinically indicated.  
A PK profile for ALM201 will be taken on Days 1, 3 and 18 of Cycle 1 and on Day 18 of Cycles 2, 
4, 6 and 8.  Pre-dose samples will also be taken on Cycles 2-8 on Day 1. 
All patients will be asked to provide consent for access to archived tumour tissue where available, 
and where possible, fresh biopsies will be taken pre-dose and again during the study where the 
patient has a documented tumour response and/or at the point of disease progression to allow for 
potential biomarker and pharmacodynamic assessment.  In Part 2, access to a tumour biopsy sample 
will be required to confirm each patient’s eligibility for the study (see Inclusion Criterion 2).  A fresh 
biopsy will be preferable for this purpose; however, where it is not possible to obtain this, 
confirmation of the angiogenesis signature may be performed on archived tumour tissue during 
Screening.  In Part 2, there will also be additional biomarker/PD assessments in blood and ascites.  In 
both parts of the study, any remaining samples obtained for biomarker/PD assessment will be 
retained for potential future analysis. 
Patients will be withdrawn from the study at the point of receiving their last dose of ALM201.  
However, all patients will be asked to participate in a protocolled follow up assessment 4 weeks after 
their last dose for safety assessments.  Furthermore, patients will continue to be followed up either in 
the study clinic or by telephone contact every 8 weeks (Schedule of Study Assessments) for up to 
approximately a 2 year period, to check their disease (survival) status and commencement of next 
anti-cancer treatment.   
Inclusion/Exclusion Criteria: 
Part 1 will enrol patients with advanced solid tumours in whom treatment with an anti-angiogenic 
agent is appropriate.  Part 2 will enrol patients with ovarian cancer, screened using an angiogenesis 
gene signature, that have failed to respond to, or have relapsed following standard therapy. 
Inclusion Criteria  
(i) Part 1 Specific Inclusion Criterion 
1.
Patients with histologically and/or cytologically confirmed advanced solid tumour for whom
no standard effective therapy is available or felt likely to be of limited efficacy and in whom a
rationale for use of an anti-angiogenic treatment approach exists. Note: Previous use of anti-
angiogenic therapy is allowed if tolerated
(ii) Part 2 Specific Inclusion Criterion 
2.
Patients with advanced ovarian cancer, who are intolerant of or whose tumour is resistant to
platinums and who have failed to respond to, or have relapsed following, standard therapy and whose
tumour has a proangiogenic profile as assessed by the angiogenesis gene signature test. Note:
Previous use of anti-angiogenic therapy is allowed if tolerated.

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(iii) General Inclusion Criteria for all Patients 
3.
Adult patients defined by age ≥16 years at time of consent.
4.
Evaluable disease, either measurable on imaging, or with informative tumour marker(s), as
assessed by RECIST 1.1 (Eisenhauer et al, 2009i) or other relevant response assessment
criteria for tumour type.
5.
Recovery from previous treatment to baseline or CTCAE ≤ Grade 1, as determined by
CTCAE v4.03 criteria (Appendix B), of reversible toxicities related to prior treatment, with
the exception of alopecia, lymphopenia, other non-clinically significant adverse events;
recovery from previous radiotherapy other than residual cutaneous effects or stable < Grade 2
gastrointestinal toxicity; complete recovery from surgery other than stable < Grade 2 toxicity.
6.
Eastern Collaborative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 (Appendix
A).
7.
Laboratory values at Screening:
•
Absolute neutrophil count ≥1.5 x 109/L without colony stimulating factor support;
•
Platelets ≥100 x 109/L;
•
Haemoglobin ≥9 g/dL (not transfusion dependent);
•
Total bilirubin <1.5 times the upper limit of normal (ULN) (unless due to Gilbert’s
syndrome where it should be ≤ 2.5 x ULN);
•
AST (SGOT) ≤2.5 times the ULN;  ALT (SGPT) ≤2.5 times the ULN;  ≤5 x ULN for
patients with advanced solid tumours with liver metastases;  patients with confirmed
bony metastases will be permitted on study with isolated elevations in ALP < 5 times the
ULN;
•
Serum creatinine  1.5 x ULN or estimated glomerular filtration rate (GFR) of >50
mL/min based on the Cockcroft-Gault formula (Appendix D);
•
Normal coagulation (elevated INR, prothrombin time or APTT <  1.3 x ULN range acceptable);
•
Urine protein ≤2+ (as measured by dipstick).
8.
Negative urine or blood human chorionic gonadotropin (hCG) test during Screening and
within 7 days of Cycle 1, Day 1 in women of childbearing potential (defined as women ≤ 50
years of age or history of amenorrhea for ≤ 12 months prior to study entry).  Sexually active
male and female patients of childbearing potential must agree to use an effective method of
birth control e.g. barrier methods with spermicides, oral or parenteral contraceptives and/or
intrauterine devices, during the entire duration of the study and for 6 months after final
administration of ALM201.  Note that sterility in female patients must be confirmed in the
patients’ medical records and can be defined as any of the following: surgical hysterectomy
with bilateral oophorectomy, natural menopause with menses >1 year ago; radiation induced
oophorectomy with last menses >1 year ago; chemotherapy induced menopause with 1 year
interval since last menses.

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9.
Ability to give written, informed consent prior to any study-specific Screening procedures,
with the understanding that the consent may be withdrawn by the patient at any time without
prejudice.
10.
Patient is capable of understanding the protocol requirements, is willing and able to comply
with the study protocol procedures, and has signed the informed consent document.
Exclusion Criteria for all Patients 
1.
History of inability to tolerate anti-angiogenic therapies e.g. increased blood pressure (BP),
proteinuria, prior thromboembolic events.
2.
Previous history of bowel obstruction, clinical evidence of gastro-intestinal obstruction, large
burden of peritoneal disease or evidence of bowel involvement on computed tomography.
3.
Patents has received:
a) any chemotherapy regimens (including investigational agents) with delayed toxicity within
4 weeks (6 weeks for prior nitrosourea or mitomycin C) of Cycle 1, Day 1, or received 
chemotherapy regimens given continuously or on a weekly basis which have limited potential 
for delayed toxicity within 2 weeks of Cycle 1, Day 1. 
b) radiotherapy, immunotherapy or biological agents (includes investigational agents) within
4 weeks of Cycle 1, Day 1.  Localised palliative radiotherapy is permitted for symptom 
control. 
4.
Documented, symptomatic or uncontrolled intracranial metastases or primary intracerebral
tumours.
5.
Cancer with leptomeningeal involvement.
6.
On therapeutic anti-coagulation (aspirin dosing ≤100 mg per oral (PO) daily allowed).
7.
Previous malignancy, except for non-basal-cell carcinoma of skin or carcinoma-in-situ of the
uterine cervix, unless the tumour was treated with curative intent more than 2 years prior to
study entry.
8.
History of clinically significant cardiac condition, including uncontrolled hypertension (BP
>140/90 mmHg, despite medical therapy); left ventricular systolic dysfunction (ejection
fraction (<55 %) on echocardiography) with or without heart failure symptoms;  history of an
ischaemic cardiac event within 3 months of study entry (myocardial infarction, acute
coronary syndrome); QT interval prolongation (QTcF, Fridericia’s Correction of >450 ms on
screening 12-lead ECG); clinically significant cardiac arrhythmia within 3 months of study
entry.  Note: ventricular tachycardia, ventricular fibrillation, supraventricular tachycardia,
atrial fibrillation without adequate heart rate control, atrial fibrillation with adequate heart
rate control with or without medication or other treatment, are not an exclusion.
9.
Known human immunodeficiency virus positivity.
10.
Active hepatitis B or C or other active liver disease (other than malignancy).
11.
Any active, clinically significant, viral, bacterial, or systemic fungal infection within 4 weeks
prior to Cycle 1, Day 1.

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12.
Any evidence of severe or uncontrolled systemic conditions or any other issues which make it
undesirable for the patient to participate in the study or which could jeopardize compliance
with the protocol.
Route of Administration, Dose Schedule and Duration: 
ALM201 administered as a SC injection with a maximum administration volume of 1.0 mL per 
injection.  Each 1 ml injection will contain 100 mg ALM201.  A maximum of 3 x 1.0 mL injections 
may be given for any single dose, therefore the MFD will be 300 mg.  The starting dose level of 
ALM201 is 10 mg given on Days 1-5, 8-12 and 15-19 of a 21-day cycle.  The SC injection may be 
given in the abdomen, leg or arm following local administration guidelines including the use of 
premedication as required for local injection site reactions.  The dose levels assessed in this study i.e. 
the dose and dosing administration schedule, may be adjusted following the study dose escalation 
rules, based on review of on-going evaluation of safety, PK and PD data generated during the study. 
Statistical Methods: 
There will be no formal statistical analysis in the dose-escalation phase this study.  Results will be 
listed and summarised using descriptive statistics.  In Part 2, response rate will be assessed and 
summarised and an exact 95% confidence interval (CI) calculated.  Analyses will be performed on 
the whole population plus those who have and have not been previously exposed to anti-angiogenics 
and those who have and not been exposed to tubulin-targeting agents before entry to this trial. 

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SCHEDULE OF STUDY ASSESSMENTS 
(i) 
Schedule of Assessments for Starting Dose Administration Schedule: Day 1-5, 8-12 and 15-19 of a 21-day dosing schedule 
Screening 
Cycle 1 (21 d cycle) 
Cycle 2 – 4 (21 d cycle) 
Cycle 5 – 8 (21 d cycle) 
Final 
Study 
Visit11 
Long-
term 
Follow 
Up  
Day 
Day 
Day 
-28 to 0 
1 
2 
3-5 
8 
9-12 
15 
16-19 
22/110 
2-5 
8 
9-12 
15 
16-19 
22/110 
2-5 
8 
9-12 
15 
16-19 
22/110 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Inclusion/exclusion 
X 
ECOG PS 
X 
X 
X 
X 
X 
Physical examination1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X  
X 
 X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (resting 12-lead)3 
X 
X 
X 
X 
X 
Clinical chemistry* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram 
X 
Haematology  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis* 
X 
X 
X 
X 
X 
Tumour assessment (radiological) 4 
X 
X4 
X4 
X4 
X4 
Tumour assessment (serum marker)4 
X 
X 
X 
X 
X4 
X4 
Immunogenicity  assessment  
X 
X 
X 
X 
X 
Biomarker/PD assessment (biopsy)5 
X 
X - up to 2 post-treatment samples 
Biomarker/PD assessment (blood sample)6 
X 
X - up to 12  post-treatment samples 
Biomarker/PD assessment (ascites)7 
(X) 
(X - up to 5  post-treatment samples) 
Biomarker (germ-line DNA) testing8 
(X) 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALM201 administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics9 
X 
X 
X  
 X 
X 
X  
X 
X  
(X) 
Long-term follow up12 
X 

Almac Discovery 
Confidential 
ALM201/0001 F2.0 
24 Sep 14 
Footnotes - General 

Assessments made on Day 1 of each cycle are to be conducted prior to ALM201 administration, unless specified otherwise.

Additional assessments may be conducted as clinically indicated.

(X) denotes an assessment not applicable to all patients.

A tolerance of +/-1 day will be permitted for all study visits and a tolerance of -1 day for all assessments relative to the study visit, unless specified otherwise.
*
female patients, if fertile, will require a serum pregnancy test at Screening and urine pregnancy on Day 1 of each cycle
Assessment Specific 
1.
Patient’s height will be recorded at Screening.  A full physical examination is required at Screening and prior to Day 1 of each cycle; Symptom-directed physical
examination is acceptable at other time-points. Weight will be recorded at Screening and on Day 1 of each cycle.
2.
On each hospital administration day, vital signs (heart rate, BP, temperature and respiration rate) will be assessed pre-dose and up to 1 hour after the ALM201 injection.
Patient status will be monitored during ALM201 administration and repeat vital signs will be taken if needed.
3.
On Cycle 1, Day 1 a resting 12-lead ECG will be conducted pre-dose and 30 mins (+/- 15 mins) after ALM201 injection.  On Day 1 of all other cycles, a resting 12-lead
ECG will be conducted pre-dose only.
4.
CT or MRI performed at Screening and up to 7 days prior to start of Cycle 3, 5, 7 and at the end of Cycle 8.   Note that where there is a rationale for assessment of bone
lesions, these assessments will be performed as part of the CT or MRI assessment and will not require additional radiological bone scan assessment.
Other informative markers e.g. CA-125, PSA, photographs of melanoma skin lesions, may be taken as appropriate on Day 1 of each cycle.
Additional scans may be performed to confirm a Complete Response (CR) or Partial Response (PR) or disease progression (PD) as per appropriate response assessment
guidelines.  Any requirement for confirmatory scans will typically be performed at the next protocolled assessment time point.  Other assessments e.g. whole body MRI
or PET, are not protocol mandated, but may be performed as clinically indicated and at request of Investigator.
5.
Patients with available archived biopsy samples will consent to provide these for biomarker/PD evaluation.  The study will encourage taking fresh biopsies for
biomarker/PD evaluation at Screening and post-treatment upon tumour response and/or at the point of disease progression.  Although optional, every effort should be
made to collect fresh pre and post-dose biopsy samples from patients – particularly in Part 2 - and imaging techniques may be used to facilitate this process.
6.
Assessment of biomarker/PD activity from blood samples taken to obtain serum, plasma, PBMC or CTCs,  may be conducted in all patients between Screening, Cycle 6
and Final Study Visit, with no more than 2 samples taken on any study day, 4 in any treatment cycle, and 13 in total during 6 cycles (including Screening and Final Study
Visit).  Time-points may vary depending on the assay and method of analysis.
7.
Assessment of biomarker/PD activity in ascites may be conducted in relevant patients who are undergoing draining of ascites as part of their standard of care.  This
procedure would normally be performed under ultrasound marking.  It is estimated that the study may obtain up to 6 samples over 8 cycles (including Screening and
Final Study Visit).  Actual time-points may vary within each cycle.
8.
Consenting patients will have a 10 mL blood sample taken for preparation of a germ-line DNA sample at Screening (recommended time-point only).

Almac Discovery 
Confidential 
ALM201/0001 F2.0 
24 Sep 14 
9.
Patients will have a 12-hour urine collection on Cycle 1, Day 1 for urine PK analysis.
Patients will have PK blood sampling conducted at Cycle 1 at the following sample times.  Three PK profiles may be taken: each will not exceed up to 12 samples taken
out to 24 hours post ALM201 injection.  The CRC may advise on adjusted time-points.  The maximum number of PK samples to be collected during any Cycle 1 dose
schedule will not exceed 40.  The actual time for each blood draw must be accurately recorded.  Initial sampling time points are:
Cycle 1, Day 1:
All doses (except 300mg): Predose, then 15 mins (+/- 5 mins), 45 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 3 hr (+/- 10 mins), 4 hr (+/- 10 mins), 5 hr
(+/- 10 mins) , 6 hr  (+/- 10 mins), 22 hr (+/- 1hr).
Doses of 300 mg: Predose, then 15 mins (+/- 5 mins), 45 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 3 hr (+/- 10 mins), 4 hr (+/- 10 mins), 5 hr (+/- 10
mins) , 6 hr  (+/- 10 mins), 7 hr  (+/- 10 mins), 8 hr  (+/- 10 mins), 22 hr (+/- 1hr).
Cycle 1, Day 3 & 18:
All doses (except 300mg): Predose, then 30mins (+/- 5 mins), 60 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 3.5 hr (+/- 10 mins), 5 hr (+/- 10 mins).
Doses of 300 mg: Predose, then 30 mins (+/- 5 mins), 60 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 4.5 hr (+/- 10 mins), 7 hr (+/- 1 hr).
Cycles 2, 4, 6 & 8, Day 18:
All doses (except 300mg): Predose, then 30mins (+/- 5 mins), 60 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 3.5 hr (+/- 10 mins), 5 hr (+/- 10 mins).
Doses of 300 mg: Predose, then 30 mins (+/- 5 mins), 60 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 4.5 hr (+/- 10 mins), 7 hr (+/- 1 hr).
A single pre-dose sample will also be taken on Cycles 2-8 on Day 1.
10.
Day 22 of Cycle 1, 2, 3, 4, 5, 6 and 7 is Day 1 of Cycle 2, 3, 4, 5, 6, 7 and 8.
11.
The Final Study Visit should be performed 30 +/-3 days after the last dose of ALM201 to enable a final safety assessment.
12.
Those patients who do not have disease progression at the Final Study Visit will be contacted every 8 weeks for up to 2 years (approximately) to check their status and
commencement of their next anticancer treatment.

Almac Discovery 
Confidential 
ALM201/0001 F2.0 
24 Sep 14 
(ii) 
Schedule of Study Assessments for Alternative Dose Schedules 
Screening 
Cycle 1 
Cycle 2 – 4  
Cycle 5 – 8  
Final Study Visit11 
Long-term Follow 
Up 
Day 
Day 
Day 
-28 to 0 
1 
2 
Other 
dosing 
days 
Weekly 
clinic 
visits 
22/110 
Other 
dosing 
days 
Weekly 
contact 
22/110 
Other 
dosing 
days 
Weekly 
contact 
22/110 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Inclusion/exclusion 
X 
ECOG PS 
X 
X 
X 
X 
X 
Physical examination1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (resting 12-lead)3 
X 
X 
X 
X 
X 
Echocardiogram 
X 
Clinical chemistry* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis* 
X 
X 
X 
X 
X 
Tumour assessment (radiological) 4 
X 
X4 
X4 
X4 
X4 
Tumour assessment (serum marker)4 
X 
X 
X 
X 
X4 
X4 
Immunogenicity  assessment 
X 
X 
X 
X 
Biomarker/PD assessment (biopsy)5 
X 
X – up to 2 post-treatment samples 
Biomarker/PD assessment (blood sample)6 
X 
X - up to 12 post-treatment samples 
Biomarker/PD assessment (ascites)7 
(X) 
(X – up to 5 post-treatment samples) 
Biomarker (germ-line DNA) testing8 
(X) 
Adverse events 
X 
X 
X 
X 
 X 
X 
X  
X 
 X  
X 
Concomitant medication 
X 
X 
X 
X 
X 
 X 
X 
 X 
X 
 X 
X 
ALM201 administration 
X (D1 + additional doses following dosing Schedule) 
X (as per dosing schedule) 
Pharmacokinetics9 
X 
X 
 X 
 X 
X  
 X 
 X 
(X)  
Long-term follow up12 
X 

Almac Discovery 
Confidential 
ALM201/0001 F2.0 
24 Sep 14 
Footnotes - General 

Assessments made on Day 1 of each cycle are to be conducted prior to ALM201 administration, unless specified otherwise.

Additional assessments may be conducted as clinically indicated.

(X) denotes an assessment not applicable to all patients.

A tolerance of +/-1 day will be permitted for all study visits and a tolerance of -1 day for all assessments relative to the study visit, unless specified otherwise.
*
female patients, if fertile, will require a serum pregnancy test at Screening and urine pregnancy on Day 1 of each cycle
Assessment Specific 
1.
Patient’s height will be recorded at Screening.  A full physical examination is required at Screening and prior to Day 1 of each cycle; Symptom-directed physical
examination is acceptable at other time-points. Weight will be recorded at Screening and on Day 1 of each cycle.
2.
On each hospital administration day, vital signs (heart rate, BP, temperature and respiration rate) will be assessed pre-dose and up to 1 hour after the ALM201 injection.
Patient status will be monitored during ALM201 administration and repeat vital signs will be taken if needed.
3.
On Cycle 1, Day 1 a resting 12-lead ECG will be conducted pre-dose and 30 mins (+/- 15 mins) after ALM201 injection.  On Day 1 of all other cycles, a resting 12-lead
ECG will be conducted pre-dose only.
4.
CT or MRI performed at Screening and up to 7 days prior to start of Cycle 3, 5, 7 and at the end of Cycle 8.   Note that where there is a rationale for assessment of bone
lesions, these assessments will be performed as part of the CT or MRI assessment and will not require additional radiological bone scan assessment.
Other informative markers e.g. CA-125, PSA, photographs of melanoma skin lesions, may be taken as appropriate on Day 1 of each cycle.
Additional scans may be performed to confirm a Complete Response (CR) or Partial Response (PR) or disease progression (PD) as per appropriate response assessment
guidelines.  Any requirement for confirmatory scans will typically be performed at the next protocolled assessment time point.  Other assessments e.g. whole body MRI
or PET, are not protocol mandated, but may be performed as clinically indicated and at request of Investigator.
5.
Patients with available archived biopsy samples will consent to provide these for biomarker/PD evaluation.  The study will encourage taking fresh biopsies for
biomarker/PD evaluation at Screening and post-treatment upon tumour response and/or at the point of disease progression.  Although optional, every effort should be
made to collect fresh pre and post-dose biopsy samples from patients – particularly in Part 2 - and imaging techniques may be used to facilitate this process.
6.
Assessment of biomarker/PD activity from blood samples taken to obtain serum, plasma, PBMC or CTCs,  may be conducted in all patients between Screening, Cycle 6
and Final Study Visit, with no more than 2 samples taken on any study day, 4 in any treatment cycle, and 13 in total during 6 cycles (including Screening and Final Study
Visit).  Time-points may vary depending on the assay and method of analysis.
7.
Assessment of biomarker/PD activity in ascites may be conducted in relevant patients who are undergoing draining of ascites as part of their standard of care.  This
procedure would normally be performed under ultrasound marking.  It is estimated that the study may obtain up to 6 samples over 8 cycles (including Screening and
Final Study Visit).  Actual time-points may vary within each cycle.
8.
Consenting patients will have a 10 mL blood sample taken for preparation of a germ-line DNA sample at Screening (recommended time-point only).

Almac Discovery 
Confidential 
ALM201/0001 F2.0 
24 Sep 14 
9.
Patients will have a 12-hour urine collection on Cycle 1, Day 1 for urine PK analysis.
Patients will have PK sampling conducted at Cycle 1 at the following sample times.  Three PK profiles may be taken: each will not exceed up to 12 samples taken out to
24 hours post ALM201 injection.  The CRC may advise on adjusted time-points.  The maximum number of PK samples to be collected during any Cycle 1 dose schedule
will not exceed 40.  The actual time for each blood draw must be accurately recorded.  Initial sampling time points are:
Cycle 1, Day 1: 
All doses (except 300mg): Predose, then 15 mins (+/- 5 mins), 45 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 3 hr (+/- 10 mins), 4 hr (+/- 10 mins) , 5 hr 
(+/- 10 mins) , 6 hr  (+/- 10 mins), 22 hr (+/- 1hr). 
Doses of 300 mg: Predose, then 15 mins (+/- 5 mins), 45 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 3 hr (+/- 10 mins), 4 hr (+/- 10 mins), 5 hr (+/- 10 
mins), 6 hr (+/- 10 mins), 7 hr  (+/- 10 mins), 8 hr  (+/- 10 mins), 22 hr (+/- 1hr). 
Cycle 1, Day 3 & 18:  
All doses (except 300mg): Predose, then 30mins (+/- 5 mins), 60 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 3.5 hr (+/- 10 mins), 5 hr (+/- 10 mins). 
Doses of 300 mg: Predose, then 30 mins (+/- 5 mins), 60 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 4.5 hr (+/- 10 mins), 7 hr (+/- 1 hr). 
Cycles 2, 4, 6 & 8, Day 18: 
All doses (except 300mg): Predose, then 30mins (+/- 5 mins), 60 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 3.5 hr (+/- 10 mins), 5 hr (+/- 10 mins). 
Doses of 300 mg: Predose, then 30 mins (+/- 5 mins), 60 mins (+/- 5 mins), 1.5 hr (+/- 10 mins), 2 hr (+/- 10 mins), 4.5 hr (+/- 10 mins), 7 hr (+/- 1 hr). 
A single pre-dose sample will also be taken on Cycles 2-8 on Day 1. 
10.
Day 22 of Cycle 1, 2, 3, 4, 5, 6 and 7 is Day 1 of Cycle 2, 3, 4, 5, 6, 7 and 8.
11.
The Final Study Visit should be performed 30 +/-3 days after the last dose of ALM201 to enable a final safety assessment.
12.
Those patients who do not have disease progression at the Final Study Visit will be contacted every 8 weeks for up to 2 years (approximately) to check their status and
commencement of their next anticancer treatment.

Almac Discovery 
Confidential 
ALM201/0001 F2.0 
24 Sep 14 
(iii) Schedule of Assessments for Cycle 9 onwards 
Cycle 9 onwards 
Final Study 
Visit6 
Long-term 
Follow Up 
Day 22/15 
Dosing days 
Weekly contact 
ECOG PS 
X 
X 
Brief physical examination1 
X 
X 
Vital signs2 
 X  
X 
ECG (resting 12-lead) 
X 
Clinical chemistry* 
X 
X 
Haematology  
X 
X 
Coagulation 
X 
Urinalysis* 
X 
Tumour assessment (radiological)3 
X3 
X3 
Tumour assessment (serum marker)3 
X 
X 
Immunogenicity 
X 
X 
Biomarker/PD assessment (biopsy)4 
X  
Adverse events 
X 
X 
X 
Concomitant medication 
X 
X 
X 
ALM201 administration 
X 
Long-term follow up7 
X 

Almac Discovery 
Confidential 
ALM201/0001 F2.0 
24 Sep 14 
Footnotes - General 

Assessments made on Day 1 of each cycle are to be conducted prior to ALM201 administration, unless specified
otherwise.

Additional assessments may be conducted as clinically indicated.

(X) denotes an assessment not applicable to all patients.

A tolerance of +/-1 day will be permitted for all study visits and a tolerance of -1 day for all assessments relative
to the study visit, unless specified otherwise.
*
female patients, if fertile, will require a serum pregnancy test at Screening and urine pregnancy on Day 1 of
each cycle
Assessment Specific 
1.
Symptom-directed physical examination. Weight will be recorded on Day 1 of each cycle.
2.
On each hospital administration day, vital signs (heart rate, BP, temperature and respiration rate) will be
assessed pre-dose and up to 1 hour after the ALM201 injection.  Patient status will be monitored during
ALM201 administration and repeat vital signs will be taken if needed.
3.
CT or MRI performed at Screening and up to 7 days prior to start of every 4 cycles.  Note that where there
is a rationale for assessment of bone, these assessments will be performed as part of the CT assessment and
not require additional radiological bone scan assessment.
Other informative markers e.g. CA-125, PSA, photographs of melanoma skin lesions, may be taken as
appropriate on Day 1 of each cycle.
Additional scans may be performed to confirm a Complete Response (CR) or Partial Response (PR) or
disease progression (PD) as per appropriate response assessment guidelines.  Any requirement for
confirmatory scans will typically be performed at the next protocolled assessment time point.  Other
assessments e.g. whole body MRI or PET, are not protocol mandated, but may be performed as clinically
indicated and at request of Investigator.
4.
A post-treatment biopsy should be taken where possible if the patient has disease progression.
5.
Day 22 of Cycle 9, 10, 11, 12, etc is Day 1 of Cycle 10, 11, 12, 13, etc.
6.
The Final Study Visit should be performed 30 +/-3 days after the last dose of ALM201 to enable a final
safety assessment.
7.
Those patients who do not have disease progression at the Final Study Visit will be contacted every 8
weeks for up to 2 years (approximately) to check their status and commencement of their next anticancer
treatment.