Clinical trial NCT03427073
Conditions: Solid Tumors Ovarian Cancer
Sponsor: Almac Discovery
Start date: 2015-04-27; Completion date: 2017-03-13
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
ALM201/0001 is a Phase I, open-label, dose-escalation study of the safety, tolerability and pharmacokinetics (PK) of ALM201.

Part 1 will be a dose-escalation study. Patients with advanced solid tumours will receive daily doses of ALM201 on Days 1-5, 8-12 and 15-19 in 21 day cycles.

Part 2 will be a dose-expansion of the Maximum Tolerated Dose (MTD) determined in Part 1. Patients with advanced ovarian cancer will be enrolled with the main objective to determine the recommended Phase II dose.

Detailed description:
ALM201 is a peptide with anti-angiogenic activity in a range of in-vitro and ex-vivo models. ALM201/0001 is a Phase I, multicentre, open-label, dose-escalation study of the safety, tolerability and pharmacokinetics (PK) of ALM201. The study is divided into two parts.

Part 1 will enrol patients with advanced solid tumours. Patients will receive subcutaneous injection of ALM201 on Days 1-5, 8-12 and 15-19 in 21 day cycles. Patients can receive up to 8 cycles of treatment. Enrolment will follow an accelerated dose-escalation schedule until grade 2 drug-related adverse events are observed, at this point the 3+3 enrolment design will be used. There will be at least 1 week stagger between the first and subsequent patients in a new cohort dose. Dose increments will not exceed 100% escalation and will be guided by data generated from previous cycles. The dose and possibly the schedule will be adjusted to determine the Maximum Tolerated Dose (MTD).

Part 2 will enrol patients with advanced ovarian cancer whose tumour has a proangiogenic profile as assessed by an angiogenesis gene signature biomarker. Patients will receive ALM201 at a dose and schedule established in Part 1.

Patients will undergo safety and tumour assessments as well as blood draws for PK profiling. The safety assessments will involve physical examination, vital signs, biochemistry and haematology laboratory screens as well as immunogenicity testing. Tumour assessments will involve computed tomography (CT) or magnetic resonance imaging (MRI) scans at screening and after every 2 cycles during cycles 1 -8. Patients will be asked to provide consent for access to archived tumour tissue and for fresh biopsies to be taken at pre-dose, tumour response and/or point of disease progression for potential biomarker and pharmacodynamic assessments. PK profiling will be carried out in Cycles 1, 2, 4, 6 and 8.

Arms: arm 1: Part 1 - Dose-escalation of ALM201 in patients with advanced solid tumours

Daily dosing of ALM201 on Days 1-5, 8-12 and 15-19 of 21 day cycle. Escalating dose cohorts arm 2: Part 2 - Dose-expansion of ALM201 Maximum Tolerated Dose (MTD) in patients with advanced ovarian cancer

Daily dosing of ALM201 on Days 1-5, 8-12 and 15-19 of 21 day cycle at the MTD determined in Part 1
Interventions: intervention 1: ALM201
Intervention descriptions: intervention 1: Drug: ALM201 administered subcutaneously

Protocol documents:
Prot_000.pdf: 
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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.

SAP_001.pdf: 
 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1 
Page 1 of 27
15Jun2017 
 
  
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A phase I open-label multicentre dose-escalation study of subcutaneous  
ALM201 in patients with advanced ovarian cancer  
and other solid tumours: Part 1 – Dose Escalation 
 
 
Study Protocol:  
ALM201/0001 
 
 
Study Drug(s):  
ALM201 
 
 
EudraCT No:   
2014-001175-31 
 
 
 
Author(s):
Melissa Hays
Document Status:
Final 1.0
Version Dates: 
Version 1 Draft 2: 01Aug2017 
 
 
 
STATEMENT OF CONFIDENTIALITY  
This Statistical Analysis Plan is the property of Chiltern and contains confidential information. Please 
ensure that the confidentiality and privacy of clients, Chiltern employees, subjects or others is 
managed in accordance with the current versions of PMIS001 Data Privacy Policy and SOP CI104 
Clinical Trial Subject Confidentiality and Personal Data Privacy 
 
 
 
 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1 
Page 2 of 27
15Jun2017 
 
Contents 
ABBREVIATIONS ............................................................................................................. 3 
1 
INTRODUCTION ....................................................................................................... 4 
2 
STUDY OBJECTIVES ............................................................................................... 4 
2.1 
PRIMARY END-POINTS ............................................................................................. 4 
2.2 
SECONDARY END-POINTS ........................................................................................ 4 
2.3 
EXPLORATORY END-POINTS .................................................................................... 5 
3 
STUDY DESIGN ......................................................................................................... 5 
3.1 
DISCUSSION OF STUDY DESIGN ............................................................................... 5 
3.2 
STUDY TREATMENT ................................................................................................ 6 
3.3 
STUDY SCHEDULE .................................................................................................. 7 
3.4 
PERMITTED AND RESTRICTED CONCOMITANT MEDICATIONS/TREATMENTS............ 15 
3.5 
STUDY ANALYSIS POPULATIONS ........................................................................... 15 
3.6 
WITHDRAWN SUBJECTS ........................................................................................ 15 
3.6.1 PATIENT WITHDRAWAL OR DISCONTINUATION ...................................................... 15 
3.6.2 REPLACEMENT OF NON-EVALUABLE PATIENTS ...................................................... 16 
3.7 
SAMPLE SIZE ........................................................................................................ 16 
4 
STATISTICAL METHODOLOGY ......................................................................... 17 
4.1 
ANALYSIS CONVENTIONS ............................................................................... 17 
4.2 
DISPOSITION OF SUBJECTS .................................................................................... 18 
4.3 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS ................................................. 18 
4.3.1 DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................................... 18 
4.3.2 GENERAL MEDICAL HISTORY ............................................................................... 19 
4.3.3 CANCER HISTORY ................................................................................................. 19 
4.3.4 PRIOR AND CONCOMITANT MEDICATION ............................................................... 19 
4.4 
EXPOSURE ............................................................................................................ 19 
4.5 
EFFICACY / PRIMARY AND SECONDARY ANALYSIS ................................................ 20 
4.6 
PHARMACOKINETIC ANALYSIS .............................................................................. 20 
4.7 
ANALYSES OF SAFETY AND TOLERABILITY ............................................................ 20 
4.7.1 ADVERSE EVENTS................................................................................................. 20 
4.7.2 LABORATORY MEASUREMENTS ............................................................................ 21 
4.7.3 PHYSICAL EXAMINATIONS AND PREGNANCY TESTS ............................................... 23 
4.7.4 EASTERN CLINICAL ONCOLOGY GROUP PERFORMANCE STATUS (ECOG PS) ......... 23 
4.7.5 12-LEAD ELECTROCARDIOGRAM AND HOLTER MONITORING ................................. 23 
4.7.6 VITAL SIGNS ........................................................................................................ 23 
4.7.7 ECHOCARDIOGRAM .............................................................................................. 24 
4.7.8 FRESH AND ARCHIVAL TISSUE COLLECTION ...... ERROR! BOOKMARK NOT DEFINED. 
5 
TABLES AND LISTINGS ........................................................................................ 25 
5.1 
TABLE FORMAT .................................................................................................... 25 
5.2 
CONVENTIONS ...................................................................................................... 25 
 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1 
Page 3 of 27
15Jun2017 
 
Abbreviations 
 
AE 
adverse event 
AUC 
area under the plasma concentration versus time curve 
BP 
blood pressure 
CA 
Competent Authority/ies 
CA-125 
cancer antigen-125 
CEA 
Carcinoembryonic antigen 
Cmax 
maximum plasma concentration  
Cmin 
minimum observed concentration 
CR 
complete response 
CRC 
Cohort Review Committee 
CRF  
case report form 
CT  
computed tomography 
CTC 
circulating tumour cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT  
dose limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
LVEF 
Left Ventrical Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD  
maximum tolerated dose 
NCI 
National Cancer Institute 
PBMC 
peripheral blood mononuclear cells 
PharmD 
pharmacodynamic(s)  
PD 
progressive disease 
PK 
pharmacokinetic(s) 
PR 
partial response 
PS 
performance status 
PSA 
prostate-specific antigen 
PT 
Preferred Term 
QTcF 
QT interval corrected for Fridericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SAE  
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SOC 
System Organ Class 
tmax 
time to reach maximum concentration 
UK 
United Kingdom 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1 
Page 4 of 27
15Jun2017 
 
1 Introduction 
This document presents the statistical analysis plan (SAP) for ALMAC, Protocol No. 
ALM201/0001: A phase I open-label multicentre dose-escalation study of subcutaneous 
ALM201 in patients with advanced ovarian cancer and other solid tumours. This analysis 
plan is based on the final protocol dated 24Sep2014. The study was to be a two-part study, 
but the sponsor decided to halt the study at the end of part 1. The SAP provides the 
description of the analysis for the final analyses of Part 1. The Pharmacokinetic Analysis will 
be conducted separately and presented in a separate document. 
 
2 Study Objectives 
 
2.1 Primary Objectives 
The primary objective of this study is/are: 
 To characterise the safety and tolerability of ALM201 
 
2.2 Secondary Objectives 
 To establish the pharmacokinetic profile of ALM201 (presented in a separate 
document) 
 To assess anti-tumour activity 
 
2.3 Exploratory Objectives 
 To assess relevant tumour biomarkers and the pharmacodynamics activity of ALM201. 
 
2.4 Primary end-points 
The primary end-points of this study are: 
 
Ongoing evaluation of Adverse Events (AEs) during treatment and follow up; 
evaluation of dose limiting toxicity (DLT) during Cycle 1  
 
Safety, pharmacokinetic (PK), pharmacodynamic (PharmD) and tumour response 
assessments 
 
2.5 Secondary end-points 
The secondary end-points of this study are: 
 
Assessment of pharmacokinetic variables (including Cmax, Cmin, Tmax,AUC) (presented 
in a separate document) 
 
Tumour response assessment by Response Evaluation Criteria in Solid Tumours 
(RECIST) 1.1(Eisenhauer et al, 2009i) and/or other relevant response assessments for 
tumour types enrolled 
 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1 
Page 5 of 27
15Jun2017 
 
2.6 Exploratory end-points 
The exploratory end-points of this study are: 
Assessment of relevant tumour biomarkers and markers of ALM201 activity 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 
 blood e.g. RASSF1 methylation, and other relevant or exploratory appropriate for 
tumour type 
 
 
3 Study Design 
 
3.1 Discussion of 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.    
 
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 
PharmD data as available.  Every new dose cohort will be evaluated for the occurrence of a 
DLT during Cycle 1 of treatment (See Section 4.2.1 of the protocol).  
 
The highest dose where ≤ 1 DLT is seen in 3 or 6 patients will be termed the maximum tolerated 
dose (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 Cohort Review Committee (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. 
 
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 (See 
Section 6 of the protocol).  Should this dose be reached without the need to de-escalate due to 
DLT, it will be termed the maximum feasible dose (MFD).   
 
Based on the review of PharmD data in conjunction with on-going safety and PK data, the CRC 
may also identify a biologically active dose (BAD) for further exploration in Part 2 of the study. 
 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1 
Page 6 of 27
15Jun2017 
 
3.2 Study Treatment 
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.  ALM201 is formulated as an aqueous solution 
containing 80mM sodium carbonate, 20mM Tris and 25mM sodium chloride, pH 6.5.   
 
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.   
 
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 
criteria for CA125 (Rustin, et al.  2011ii), prostate-specific antigen (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. 
 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1
Page 7 of 27
15Jun2017 
 
3.3 Study Schedule 
 
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/PharmD assessment (biopsy)5
X
X - up to 2 post-treatment samples
Biomarker/PharmD assessment (blood 
sample)6 
X 
X - up to 12  post-treatment samples 
  
Biomarker/PharmD 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 
 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1
Page 8 of 27
15Jun2017 
 
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/PharmD evaluation.  The study will encourage taking fresh biopsies for 
biomarker/PharmD 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/PharmD 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/PharmD 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. 
 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1
Page 9 of 27
15Jun2017 
 
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). 
 
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. 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1
Page 10 of 27
15Jun2017 
 
 
Schedule of Study Assessments for Alternative Dose Schedules 
  
Screening 
Cycle 1
Cycle 2 – 4 
Cycle 5 – 8 
Final 
Study 
Long-
term
Day
Day
Day
-28 to 0 
1 
2 
O
t
h
e
W
e
e
k
2
2
/
1
O
t
h
W
e
e
2
2
/
O
t
h
W
e
e
2
2
/
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/PharmD assessment (biopsy)5
X
X – up to 2 post-treatment samples
 
Biomarker/PharmD assessment (blood sample)6 
X 
X - up to 12 post-treatment samples 
  
Biomarker/PharmD 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


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1
Page 11 of 27
15Jun2017 
 
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/PharmD evaluation.  The study will encourage taking fresh biopsies for 
biomarker/PharmD 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/PharmD 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/PharmD 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. 
 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1
Page 12 of 27
15Jun2017 
 
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). 
 
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. 
 
 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1 
Page 13 of 27 
15Jun2017 
 
 
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/PharmD assessment 
(biopsy)4  
X  
 
Adverse events 
X 
  
X 
X 
 
Concomitant medication 
X 
  
X 
X 
 
ALM201 administration 
  
X 
  
  
 
Long-term follow up7 
  
  
  
 
X 
 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1 
Page 14 of 27 
15Jun2017 
 
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. 


 
 
Sponsor: 
Almac 
Protocol Number: 
ALM201/0001 
 
TPBS001 Version 6
CONFIDENTIAL
Effective Date: 15th March 2017 
(based on TPQA036 Version 2)  
 
Prior Effective Date: 9th October 2016
SAP version 0.1 
Page 15 of 27
15Jun2017 
 
3.4 Permitted and Restricted Concomitant Medications/Treatments  
All prescription, non-prescription, or over-the-counter medications including herbal remedies, 
dietary and nutritional supplements and complementary and alternative therapies given to, or 
taken by the patient at study entry (including Screening) and during the study must be clearly 
documented on the case report form (CRF).   
 
Any medication considered necessary for the patient’s safety and well-being may be given at 
the discretion of the Investigator(s).  
 
For treatment of DLT or any other clinically significant events, any available standard therapy 
may be used as required.  
 
Prohibited treatments are summarized below: 
 
other antineoplastic agents; 
 
concurrent radiation treatment will be permitted during this study for 
symptom control; 
 
other investigational medicinal products. 
 
3.5 Study Analysis Populations 
 
Enrolled Patients: All patients who enroll in the trial. 
Efficacy Population: All patients with at least one post-baseline tumour response assessment 
Safety Population: All patients who receive at least one dose of study drug. 
 
3.6 Withdrawn Patients 
 
3.6.1 Patient Withdrawal or Discontinuation 
Patients may withdraw from the study at any time without stating a reason and without 
prejudice to further treatment.  A Final Study Visit should be performed 30 +/-3 days after the 
last dose of ALM201 to enable follow up safety assessments and further tumour assessment 
where required.   
 
The Investigator may withdraw a patient from the study and discontinue study treatment and 
assessments at any time.  Example reasons for discontinuing a patient from this study are: 
 
 
Disease progression. 
 
The patient experiences a toxicity, including those necessitating a dose delay of 
>14 days (See Protocol Section 4.2.1), where the re-introduction of ALM201 
(including a dose reduction of ALM201), is not considered suitable.  Exceptions 
may be considered where the toxicity is not considered to be ALM201 treatment-
related.   
 


 
 
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 
Other toxicities or events, unrelated to ALM201, that would, in the Investigator’s 
opinion, prevent the patient from continuing on this trial.   
 
Protocol non-compliance.  (All documentation concerning the patient must be as 
complete as possible.  Withdrawals due to non-attendance of study visits must be 
followed-up by the Investigator to obtain the reason for where possible). 
 
Patient withdraws consent to participate in the study. 
 
Patient becomes pregnant (see Protocol, section 7.4.3) 
 
The Sponsor reserves the right to request the withdrawal of a patient due to protocol violation 
or other significant reason.  Patients who experience a toxicity event which qualifies as a DLT, 
may continue to receive ALM201 if considered safe to do so and where continued treatment is 
considered by the Investigator to be in the patient’s best interests.  The decision to continue 
treatment will be reviewed by the CRC (See Protocol Section 8.1) and will involve an 
adjustment (de-escalation) in dose or dose schedule. 
 
3.6.2 Replacement of Non-evaluable Patients 
In Part 1, patients will be replaced if they are not considered evaluable for DLT during Cycle 
1.  As a general rule during Part 1, patients will be considered evaluable for DLT during Cycle 
1 if they receive at least 80% (i.e. 12 of 15 planned doses) of their intended dose, unless this is 
due to ALM201-related toxicity.  However, this will be reviewed by the CRC on a case-by-
case basis.  For example, based on safety and PK data available, the CRC may agree that on a 
weekday dosing schedule, missing 1 dose per week on the 21-day dosing cycle is acceptable; 
whereas, missing 3 consecutive doses is not.  Furthermore, the ability to evaluate a patient who 
misses more than 80% of their intended dose due to toxicity considered to be related to 
ALM201, but which is not ultimately classed as a DLT, will be reviewed on a case-by-case 
basis.  Patients who withdraw from the study or discontinue treatment after completion of the 
first treatment cycle will not be replaced.   
 
3.7 Sample Size 
 
No formal sample size calculation was performed. 
 


 
 
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4 Statistical Methodology 
 
4.1 Analysis Conventions 
 
This section details general conventions to be used for the statistical analyses. Departures from 
these general conventions may be given in the specific detailed sections of this analysis plan.  
All data were collected using electronic case report forms (eCRFs). 
 
 For all analyses, each dose level and overall will be summarized using descriptive 
summary statistics. Each treatment group will have a cohort number and data will be 
summarized in all tables, listings, and figures by treatment or cohort number. No 
statistical comparison of dose levels will be performed. 
 
 Summary statistics will consist of the number and percentage for categorical variables, 
and the number of observations (n), mean, standard deviation (Sd), minimum, median, 
and maximum values for continuous variables. When the standard deviation cannot be 
calculated, a hyphen (-) will be used. 
 
 All mean and median values will be formatted to one more decimal place than the 
measured value on the eCRF.  Standard deviation values will be formatted to two more 
decimal places than the measured value on the eCRF.  Minimum and maximum values 
will be presented with the same number of decimal places as the measured value on the 
eCRF.  
 
 The number and percentages will be presented in the form XX (XX) where the 
percentage is in the parentheses.  Unless otherwise specified, the denominator for 
percentages will be the number of patients in a given dose level within the analysis 
population of interest.  
 
 All summary tables will include the analysis set sample size (i.e., number of patients). 
 
 Baseline is defined as the last planned assessment before the first administration of 
study drug, unless otherwise specified. Typically this will be the Cycle 1 Day.  
 
 Change from baseline will be calculated as follows:  
Change from baseline = Post-baseline value  baseline value. 
 
 Age will be calculated as the integer: (Date of informed consent – date of 
birth)/365.25, rounded down to the nearest integer. 
 
 Duration of time on study drug (days) = Date of last injection – date of first 
injection+1. 
 
 Date and time variables will be formatted as DDMMMYYYY hh:mm for presentation.  
 


 
 
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 Summary tables with present data from scheduled assessments; listings will include all 
data, sorted by date. 
 
 Tables, figures, and listings will be presented in landscape orientation. 
 
 SAS Version 9.4 or higher will be the statistical software package used for all data 
analysis.   
 
 AEs and medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 17.0.  
 
 Prior cancer therapies and prior and concomitant medications will be coded using the 
WHO Drug dictionary version March 2014. 
 
 No imputation of values for missing data will be performed, unless otherwise stated.  
 
4.2 Disposition of Patients 
 
Patient disposition will be summarized with the frequency and percentage of the following 
items: patients who enrolled (i.e., All Patients), patients who received at least one dose of study 
drug (i.e., Safety Population), patients who received at least one dose of study drug and 
completed at least one post-baseline response evaluation (i.e., Efficacy Population), the number 
of patients dosed at each cycle, patients who discontinued the study and the reasons for 
discontinuation.  
 
A summary of protocol deviations will be presented. Protocol deviations are defined in Insight 
as: 
 
Eligibility 
 
ICF Issue 
 
IP Non-compliance 
 
IP Dispensing Error 
 
Assessment not performed per protocol 
 
Failure to adhere to visit schedule 
 
Other 
 
Patient disposition, protocol deviations, and eligibility criteria (including inclusion/exclusion) 
will be presented in data listings. 
 
4.3 Baseline and Demographic Characteristics 
 
4.3.1 Demographics and Baseline Characteristics 
Demographic and baseline characteristics data will be summarized for all patients in the Safety 
population. Summary statistics will be calculated for race, ethnicity, gender, age, height (cm), 
weight (kg), left ventrical ejection fraction (LVEF) and Eastern Cooperative Oncology Group 
(ECOG) performance status at screening, as well as female reproductive status. Age will be 


 
 
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summarized as a continuous and categorical variable (≤ 55 years and > 55 years).  All 
demographic and baseline data will be presented in data listings.  
 
4.3.2 General Medical History 
General medical history will be coded using MedDRA Version 17.0 system organ class (SOC) 
and preferred term (PT). It will be summarized, sorted by alphabetical order of SOC and 
preferred term. For the table summary, a patient will only be presented once for each level of 
summarization. Medical history will be presented in a data listing. 
 
4.3.3 Cancer History 
Time from date of initial cancer diagnosis to study entry (i.e., informed consent date) (months) 
and disease-specific characteristics of primary tumour, such as histology and tumour stage will 
be summarized. 
Prior cancer therapies by number of previous regimens, duration of therapy, type of agent 
(chemo, immunotherapies, hormonal therapy, monoclonal therapy, radiation therapy and 
others), WHO ATC Level II drug class, and WHO preferred term, reason for administration, 
best response on therapy, and reason for discontinuation.  For radiotherapies, field of radiation 
and estimated radiation dose will be summarized as well. All cancer history and prior cancer 
therapies will be presented in data listings.  
 
4.3.4 Prior and Concomitant Medication and Ancillary Procedures 
All prescription, non-prescription, or over-the-counter medications including herbal remedies, 
dietary and nutritional supplements and complementary and alternative therapies will be coded 
using the WHO Drug dictionary version March 2014 and classified into the default ATC code 
provided by the system.  
A prior medication is defined as any medication started and stopped prior to the first 
administration of study drug. Concomitant medications are those taken on or after the first dose 
of study drug. 
The incidence of concomitant medications by WHO ATC level II drug class and preferred term 
will be summarized and presented in alphabetical order of ATC level and preferred term for 
the Safety population. For the table summary, a patient will only be presented once for each 
level of summarization.  
All medications (prior and concomitant) and any ancillary procedures will be presented in a 
data listing. 
 
4.4 Exposure 
 
Summary of exposure will include the total number of days on study medication and total 
dose received, and, by cycle, the location sites of injection, the total amount injected per visit 
and dose modification details. All study drug exposure information will be presented in a 
listing. 
 


 
 
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4.5 Efficacy / Primary and Secondary Analysis 
 
As this is a phase 1 study, the extent of efficacy data is expected to be limited. However, a 
summary of Clinical benefit, by RECIST Version 1.1 from patients with evaluable disease will 
be generated. The summary will include the number and percent of patients, overall and by 
cohort with: 
 
Complete response (CR) 
 
Partial Response (PR) 
 
Overall Response (CR+PR) 
 
Stable Disease (SD) 
 
Disease Control Rate (SD+CR+PR) 
 
Progressive Disease (PD) 
 
Not Evaluable 
 
Listings detailing the target, non-target, overall response assessments reported, and survival 
follow-up will be presented. 
 
4.6 Pharmacokinetic Analysis 
This analysis will be described in a separate document and the results presented in a separate 
document as well. 
 
4.7 Analyses of Safety and Tolerability 
 
All safety analysis will be performed on Safety Population. 
 
4.7.1 Adverse Events 
 
Adverse events will be summarized in terms of treatment-emergent adverse events (TEAEs) 
where treatment-emergent is defined as any AE that occurs after administration of the first dose 
of study drug and through 28 days after the last dose of study drug, any event that is considered 
study drug-related regardless of the start date of the event, or any event that is present at 
baseline but worsens in intensity or is subsequently considered study drug-related by the 
Investigator. Treatment-related TEAEs include those events considered by the investigator to 
be possibly, probably, or definitely related to study drug. 
 
Adverse Events will be coded using MedDRA version 17.0 and graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03. The incidence of TEAEs will be summarized by MedDRA System Organ Class (SOC), 
Preferred Term (PT) and NCI CTCAE grade. Tables summarizing the incidence of TEAEs will 
be generated for each of the following: 
 
 
Treatment Emergent AE Overview; 
 
All TEAEs by SOC and PT; 
 
TEAE by SOC, PT, and CTCAE Grade 
 
Treatment-Related TEAEs by SOC and PT; 


 
 
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 
Treatment-Related TEAEs by SOC, PT and CTCAE grade; 
 
Treatment Emergent Serious Adverse Events by SOC and PT; 
 
Treatment Emergent Serious Adverse Events by SOC, PT and CTCAE grade; 
 
Treatment-Related Treatment Emergent Serious AEs by SOC and PT; 
 
Treatment-Related Treatment Emergent Serious Adverse Events by SOC, PT and 
CTCAE grade; 
 
Treatment-Emergent Adverse Events ≥ Grade 3 by SOC and PT 
 
Treatment-Related Treatment-Emergent Adverse Events ≥ Grade 3 by SOC and 
PT 
 
TEAEs leading to discontinuation of study drug by SOC and PT 
 
TEAEs leading to modification/interruption of study drug by SOC and PT 
 
Dose Limiting Toxicities by SOC and PT 
 
Fatal TEAEs by SOC and PT 
If a patient experiences multiple episodes of the same event, the patient will only be counted 
once for that particular event.  In the case of partially missing AE start dates, all available date 
information will be used to determine whether or not the AE is treatment-emergent. Adverse 
events with completely missing start dates will be considered to be treatment-emergent unless 
the stop date is known to be prior to the first administration of the study drug.  
 
For tables that are presented by maximum grade, if a patient experiences multiple episodes of 
the same event, the event with the maximum grade will be used.   
 
For tables that are presented by strongest relationship, if a patient experiences multiple episodes 
of the same event, the event with the strongest relationship to study drug will be used.  
 
Deaths, serious adverse events (SAEs), and AEs resulting in study drug discontinuation also 
will be tabulated. The AE summaries will be presented in alphabetical order of SOC and 
preferred term. 
 
All AEs, including treatment-emergent and non-treatment-emergent AEs, will be presented in 
data listings. 
 
4.7.2 Laboratory Measurements 
 
Scheduled clinical chemistry, hematology, coagulation, urinalysis and tumour biomarker, and 
other laboratory assessments will be collected and analyzed according to the study center’s 
standard procedure. The laboratory assessments collected will be the following: 
 
Clinical chemistry 
Haematology, including coagulation screen 
Calcium 
Red cell count 
Total protein 
Hemoglobin 
Albumin 
Hematocrit 


 
 
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Clinical chemistry 
Haematology, including coagulation screen 
Total bilirubin 
Absolute reticulocyte count 
Alanine transaminase (ALT, SGPT) 
Platelet count 
Aspartate transaminase (AST, SGOT) 
White blood cells 
Alkaline phosphatase 
Leucocyte differential count (% & absolute) 
Glucose (random) 
International normalized ratio or prothrombin 
time 
Sodium 
Activated partial thromboplastin time  
Potassium 
 
Bicarbonate 
 
Chloride 
 
Magnesium 
 
Urea 
 
Creatinine 
 
Phosphate 
 
Uric acid 
 
Pregnancy test as required (Screening) 
 
 
 
 
 
Urinalysis 
 
Glucose* 
 
Protein* 
 
Bilirubin* 
 
Ketones* 
 
Blood* 
 
pH 
 
Specific gravity & 
Microscopic examination when indicated 
 
Pregnancy test as required 
 
 
* Assessed categorically only 
 
Creatinine clearance should be calculated using the Cockroft-Gault Formula, which is given below: 
 
1.25 x (140 – age) x weight (kg) 
Males:    
 
 
Serum creatinine (µmol/l) 
 
 
 
1.05 x (140 – age) x weight (kg) 
 
Females:    
 
 
Serum creatinine (µmol/l) 


 
 
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Cockroft DGM, 1976iii 
 
 
Lab values will be expressed in SI units.  Any lab data collected from local labs that are nont 
in SI units will be converted in the analysis dataset to SI units prior to summarization. Actual 
and change from baseline summary statistics will be presented at each scheduled time point of 
the study for each lab parameter. Laboratory parameters with categorical results will be 
summarized with the number and percentage of patients. Repeat and unscheduled 
measurements will not be summarized; however, they will be in the data listings.  
 
Shift tables from baseline result to worst post-baseline result will be generated.  In the shift 
tables, results will be categorized as low, normal, high, including low clinically significant and 
high clinically significant when available. If a patient has both low and high post-baseline 
values, the summary table will display the result with the greatest absolute departure from the 
normal limits for that parameter.  The denominators for the percentages will be the number of 
patients with non-missing data at both the baseline and any post-baseline time point for a 
parameter. 
 
4.7.3 Physical Examinations and Pregnancy Tests 
 
All PE results will be presented in data listings. No pregnancy testing was conducted during 
this study. 
 
4.7.4 Eastern Clinical Oncology Group Performance Status (ECOG PS) 
 
Frequencies and percentage of patients with each ECOG performance status (PS) will be 
summarized as a categorical variable by cycle and worst status overall. All ECOG PS will be 
presented in a data listing. 
 
4.7.5 12-Lead Electrocardiogram  
 
The actual ECG measurements at each study evaluation time point along with the 
corresponding change from baseline calculation will be summarized for heart rate, PR, QRS, 
QT and QTc calculated using Fridericia’s correction. 
 
Overall ECG interpretations will be summarized using a shift table from baseline to the worst 
post-baseline interpretation. ECG interpretations will be reported as normal, Abnormal Not 
Clinically Significant (NCS), or Abnormal Clinically Significant (CS). 
 
The denominators for the percentages will be the number of patients with non-missing data at 
both the baseline and any post-baseline visit. Additionally, the number and percentage of 
patients with elevated QT interval corrected for Fridericia’s formula (QTcF) (> 450 and > 470) 
will be summarized by visit.   
 
All 12-Lead ECG data will be presented in a data listing. 
 
4.7.6 Vital Signs  
 


 
 
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The actual vital signs measurements at each scheduled time point along with the corresponding 
change from baseline calculations will be summarized for systolic/diastolic blood pressure 
(mmHg), pulse (beats/min), temperature (°C), respiratory rate (breaths/min), and weight (kg). 
  
All vital signs will be presented in a data listing. 
 
4.7.7 Echocardiogram  
 
Listings of the left ventricular ejection fraction (LVEF) obtained by echocardiogram or 
MUGA, at screening, will be presented in listings. 
 
4.7.8 Immunogenicity and Pharmacodynamic Samples 
 
Listings of all samples collected to assess biomarker and PharmD activity will be presented. 
 Ascites Samples 
 Blood Samples for Biomarkers 
 Biopsy Samples Biomarkers 
 Immunogenicity Samples 
 Serum Tumour Marker Samples 
 


 
 
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5 Tables and Listings 
 
5.1 Table Format 
All output will be produced using SAS version 9.1.3 or a later version. 
In the top left portion of each table/listing, a table/listing number followed by the title of the 
table/listing will be presented. After the title line, optional sub-title or population information 
can be presented. Horizontal lines will appear before and after the column heading of the 
table/listing. Footnotes will be put under the main body of text at the bottom of the page.  
The sponsor name, protocol number, programmers User ID, status of the table/listing (i.e. draft 
or final) and SAS program name will appear bottom left in a string and the page number will 
appear on the bottom right corner of each table/listing. The date and time of creation of 
table/listing will appear bottom left under the sponsor name. The source listing number will 
appear bottom left.  
A landscape layout is proposed for both table and listing presentations. 
The left and right margins of all tables and listings will be a minimum of 2.1 cm from the left 
and 1.9cm from the right. The top and bottom margins will be a minimum 2.92cm. Header and 
footer will be both 1.27 cm. 
There is no special requirement of font type and size, but an 8-point font size for tables and 7or 
8-point for listings is proposed using Courier New font. A maximum SAS line size=141 and 
page size=44 for 8-point font size, and line size=161 and page size=50 for 7-point will be used 
so as to fit on both UK and US paper sizes. 
In a listing, in the case that a patient’s record has been continued to the next page, an appropriate 
identification (e.g., the patient ID number) must be presented at the beginning of that page. 
 
5.2 Conventions 
Unless otherwise specified, in summary tables of continuous variables, the minimum and 
maximum values will be displayed to the same number of decimal places as the raw data, the 
mean and median will be presented to one extra decimal place compared to the raw data, and 
the standard deviation will be displayed to two extra decimal places compared to the raw data. 
Wherever possible, data will be decimal aligned. 
Unless otherwise specified frequency tabulations will be presented by number and percentage, 
where the percentage is presented in brackets to 1 decimal place. 
Any date information in the listing will use the date9. format, for example, 07MAY2002. In 
the listing, a unit associated with a variable will be presented only once within parentheses 
either below or next to that variable in the heading portion. If a parameter has multiple units, 
each unit will be displayed only once, as applicable. 
All tables will have their source listing referenced in a footnote. Listings should be sorted by 
treatment group, patient and visit and have the source data received by data management 
referenced in a footnote. All tables and listings will be converted into Microsoft Word 
documents and collated into two complete documents.  
 
 


 
 
Sponsor: 
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Protocol Number: 
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6 References 
 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. (2009) New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 228-247. 
 
(http://www.eortc.be/recist/documents/RECISTGuidelines.pdf) 
 
Rustin GJS, Vergote I, Eisenhauer E, et al.  (2011) Definitions for Response and Progression 
in Ovarian Cancer Clinical Trials Incorporating RECIST 1.1 and CA 125 Agreed by the 
Gynecological Cancer Intergroup (GCIG).  Int J Gynecol Cancer 21: 419-423 
 
Hinnen P and Eskens F A L M.  (2007)Vascular disrupting agents in clinical development.   
Br J Cancer. Apr 23, 96(8): 1159–1165. 
 
Eskander RN and Tewari KS (2014)  Incorporation of anti-angiogenesis therapy in the 
management of advanced ovarian carcinoma – Mechanistics, review of phase III randomized 
clinical trials, and regulatory implications  Gynecologic Oncology 132: 496-505 
 
Rustin GJS, Vergote I, Eisenhauer E, (2011).  Definitions for Response and Progression in 
Ovarian Cancer Clinical Trials Incorporating RECIST 1.1 and CA 125 Agreed by the 
Gynecological Cancer Intergroup (GCIG).  Int J Gynecol Cancer 21: 419-423 
 
Cockroft DGM. (1976) Prediction of creatinine clearance from serum creatinine. Nephron. 
16:31-41. 
 
 


 
 
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i Eisenhauer EA, Therasse P, Bogaerts J, et al. (2009) New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 228-247. 
 
(http://www.eortc.be/recist/documents/RECISTGuidelines.pdf) 
 
ii  
Rustin GJS, Vergote I, Eisenhauer E, et al.  (2011) Definitions for Response and 
Progression in Ovarian Cancer Clinical Trials Incorporating RECIST 1.1 and CA 
125 Agreed by the Gynecological Cancer Intergroup (GCIG).  Int J Gynecol Cancer 
21: 419-423 
 
iii  
Cockroft DGM. (1976) Prediction of creatinine clearance from serum creatinine. 
Nephron. 16:31-41. 
 
 
                                                          
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