Conditions: Carcinoma, Non-Small-Cell Lung Adenocarcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
The objectives of this study are to assess the safety, tolerability, pharmacokinetics and efficacy of VAL401 in the treatment of patients with locally advanced or metastatic non-small cell lung adenocarcinoma.

Detailed description:
This is a Phase II, open label study to assess the efficacy, safety and tolerability of VAL401 in the treatment of patients with locally advanced or metastatic non-small cell lung adenocarcinoma after failure of at least one prior chemotherapeutic regimen. Eligible patients will be enrolled as a single cohort and treated with VAL401, given as oral capsules. VAL401 is a formulation of Risperidone (active pharmaceutical ingredient) in a liquid lipid filled capsule.

Arms:
arm 1: Patients received VAL401 oral formulation once daily according to their level of tolerance (2 mg - 10 mg).

Interventions: intervention 1: VAL401
Intervention descriptions: intervention 1: Risperidone formulated into a liquid lipid filled capsule

Protocol document:
Prot_SAP_000.pdf: 
ValiSeek Limited
CONFIDENTIAL
Page 1 of 54
VALISEEK LIMITED
PRODUCT:
VAL401
CLINICAL STUDY PROTOCOL
A Phase II Study to Assess the Efficacy, Safety and
Tolerability of VAL401 in the treatment of patients with
locally advanced or metastatic Non-Small Cell Lung Cancer
(NSCLC) after failure of at least one prior
chemotherapeutic regimen.
Protocol No:
VAL401-001
Version No:
2.0
Version Date:
22 November 2016
Confidentiality Statement
This document contains confidential information, which is the property of ValiSeek Limited. This
information is provided to you in confidence and includes the clinical and non-clinical data on the
investigational medicinal product VAL401 relevant to the study of the product in human subjects. It is
understood that this information will not be disclosed to others without written approval by ValiSeek
Limited.


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Page 2 of 54
Sponsor Signatures
I have reviewed and approve the protocol
Signed:
Date:
Dr Suzanne Dilly, ValiSeek Limited, Chief Executive Officer
Signed:
Date:
Dr George Morris, ValiSeek Limited, Chief Operating Officer
ValiSeek Limited
c/o Valirx plc
16 Upper Woburn Place
London, WC1H 0BS
UK


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Page 3 of 54
Principal Investigator Declaration
I have read this protocol and agree that it contains all the necessary details for carrying out this study.
I will conduct the study as described and will complete the study within the time designated.   I verify
that I am suitably qualified by education, scientific and medical training and experience to conduct the
study. Documentation of my qualifications and professional affiliations are contained in my up-to-
date curriculum vitae.
I will provide the supplied copies of the protocol, including future protocol amendments, and all
information relating to non-clinical, and clinical experience when available (e.g. in updated editions
of the Investigator’s Brochure), to all staff in my unit involved in the conduct of this study.  I will
discuss this material with them to ensure that they are fully conversant with medical treatment and
study design, and that they will handle the data and information generated in the study confidentially.
I will conduct the study in accordance with GCP, the Declaration of Helsinki, and the moral, ethical
and scientific principles that justify medical research. The study will be conducted in accordance with
the relevant laws and regulations relating to clinical studies and the protection of patients.  All patients
will be informed comprehensively about the nature of the study and will give their written consent to
participate before entry into the study.  They will be informed that they may withdraw from the study
at any time.  I will use only the information sheet and consent form approved by ValiSeek and the
Ethics Committee (EC) for this study.  I will supply ValiSeek with any material written by myself
(e.g. summary of study) which is given to the EC in support of the application.
Where applicable, the patient information contained in clinic records, reports and manuscripts will be
transcribed to the case report forms (the case report form may be the original source document for
specified items).  Either  I  or  an  appointed  person  will  attest  to  the  authenticity  of  the  data  and
accuracy  and completeness of the transcription by signing the case report form.   I agree to the audit
and monitoring procedures that involve verification of such study records against original records.
Should it be requested by government regulatory agencies, I will make available additional
background data from my records, and where allowed, from the hospital or institution where the study
was conducted.
I understand that the case report forms and other data pertinent to this study are the property of
ValiSeek and are confidential.  I will supply ValiSeek (or their delegates) with the study data in such a
way that the patient cannot be personally identified.
Investigator Signature:
Date:
Print Name:
Address/Hospital:
Telephone Number:


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Other Contact Information
Full contact details for each Investigational site, the Sponsor, Medical Monitor and other key
coordinating and operational personnel involved in this clinical trial (including vendors), will be
maintained and available for reference in the Trial Master File and in each Site Study File.


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Protocol Synopsis
Protocol No:
VAL401-001
Study Title:
A Phase II Study to Assess the Efficacy, Safety and Tolerability of VAL401 in the treatment of
patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) after failure of at
least one prior chemotherapeutic regimen.
Investigational Product:
VAL401. VAL401 is a formulation of Risperidone in a lipid filled capsule for oral administration.
Phase of Development:
II
No of Sites:
2
No of Patients:
20
Study Objectives and Endpoints:
The objectives of this study are to assess the safety, tolerability, pharmacokinetics (PK) and efficacy
of VAL401 in patients with locally advanced or metastatic non-small cell lung cancer.


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Objective
Endpoint
Primary:

Progression-free survival (PFS)

As assessed by RECIST 1.1 criteria. PFS
will be defined as the time from
randomisation to disease progression (or
death if the patient died before
progression)
Secondary:

To evaluate the pharmacokinetics of
VAL401

To assess potential disease
modifying activity

To determine the safety and
tolerability of VAL401

To evaluate patient quality of life
during VAL401 treatment

Overall Survival

Assessment of pharmacokinetic variables
in collected blood samples (including Cmax,
Cmin, AUC) on Day 1 and Day 15 of Cycle
1.

Objective tumour response rates according
to RECIST 1.1 including time to objective
response and duration of objective
response; or disease control (defined as a
patient with objective response or stable
disease) according to RECIST version 1.1
including duration of disease control

Ongoing evaluation of AEs during
treatment and follow up

Changes in patient quality of life measured
by HRQoL assessment EORTC QLQ –
C30 provided in Georgian under license
from EORTC
Exploratory:

Biomarker testing

Testing of germline DNA in single blood
sample at Day 0 for biomarker assessment.
Testing of historic tumour biopsy material
where available.
Study Design:
This is a Phase II, open label study to assess the efficacy, safety and tolerability of VAL401 in the
treatment of patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) after
failure of at least one prior chemotherapeutic regimen. Eligible patients will be enrolled as a single
cohort and treated with VAL401, given as oral capsules.
Each patient will be dosed according to the schedule of: Day 1: 2 mg in a single daily dose; Day 2: 4
mg in a single daily dose; Day 3: 6 mg in a single daily dose; Day 4: 8 mg in a single daily dose; Day
5 and onwards: 10 mg in a single daily dose.
If a patient experiences a DLT, the dose will be reduced to the previous acceptable dose, and the
patient will remain on this personal MTD for the remainder of the study.
VAL401 is supplied as 5 mg and 1 mg dose capsules, each day’s individual dose composed of the
relevant combination of 1 mg and 5 mg capsules to total the required level.
All patients will remain on 10 mg as a single daily dose (or their personal MTD if reached) until they
experience disease progression or unacceptable toxicity.
Dose Limiting Toxicity


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The maximum feasible dose which may be administered is 10 mg per day.  Should this dose be
reached without the need to de-escalate the dose due to DLT, it will be termed the Maximum
Administered Dose (MAD).
Safety Evaluations will be conducted daily during the dose escalation period (a minimum of Day 1 –
Day 5 of Cycle 1), weekly for the remainder of cycle 1, and fortnightly thereafter. All events and
suspected DLTs will be graded according to the Common Terminology Criteria for Adverse Events
(CTCAE) version 4.03.
A DLT is defined as a VAL401-related Grade 3 or 4 adverse event that, in the opinion of the
Investigator represents a clinically significant hazard to the subject, with the following exceptions as
considered appropriate:

Grade 3 or 4 laboratory abnormalities, which resolve spontaneously or can be corrected with
appropriate treatment (such as electrolytes).  For example, an event returns to baseline or to
Grade 1 at the next assessment.

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.
Qualifying toxicity events must be considered to be clinically relevant e.g. in duration, and likely to
be related to treatment with VAL401.  DLT events will also be considered in terms of what is
considered to be an appropriate next escalation step: in the case where the Investigator considers a
daily escalation of 1 mg instead of 2 mg per day in the dose escalation period of Cycle 1, the toxicity
of concern should be declared a DLT.
Dose Escalation
During Cycle 1 of treatment the following escalation steps are recommended in the absence of
VAL401-related events which would lead to a more cautious dose escalation:
Cycle 1; Day
Daily Dose
Capsules administered
1
2 mg
2 x 1 mg
2
4 mg
4 x 1 mg
3
6 mg
1 x 5 mg + 1 x 1 mg
4
8 mg
1 x 5 mg + 3 x 1 mg
5 and subsequent
10 mg
2 x 5 mg
In the case where a potentially significant toxicity which is not a DLT, or a trend in toxicities seen,
considered to be related to treatment with VAL401 occur and are considered to be a precursor of a
clinically significant toxicity event; subsequent dose escalation steps in that patient may be more
conservative (1mg per day increase until MTD reached, or a 24 hour delay until the next dose increase
– at the discretion of the Investigator).  This restriction may be reversed where there is no suggestion
of a potentially clinical significant toxicity in the subsequent dose level.
Where a patient establishes a DLT, the dose should be reduced by one step, and the patient continued
on this dose for the remainder of the study providing that the DLT has been resolved.  This dose will
be noted as the patient’s personal MTD.


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Duration of treatment
A maximum of 6 treatment cycles of 28 days is permissible within the design of this study.  Patients
whose disease has not progressed and who have not withdrawn from the treatment due to
unacceptable toxicity will be able to continue to receive VAL401 at the discretion of the Investigator.
Such patients will continue to be followed up for toxicity and continued response and may be
transferred to an extended treatment protocol.
Study Assessments
The study will commence with a dosing schedule of VAL401 given orally as a capsule (or
combination of capsules) according to the dose escalation described above on all days of a four week
cycle.
Patients will visit the study sites on each day of the dose escalation period in Cycle 1, and fortnightly
thereafter for the remainder of the 6 cycles of treatment for a clinical examination, recording of AEs
and the Health related Quality of Life questionnaire (HRQoL).  Laboratory screens will be assessed
weekly during Cycle 1 and fortnightly thereafter.  Tumour assessment including imaging where
relevant will be assessed at Screening, after three cycles, and after 6 cycles. Follow up assessments
will be conducted in accordance with RECIST 1.1 (Eisenhauer 2009).
A full PK profile will be taken after the first dose on Day 1 Cycle 1 and after dosing on Day 15 Cycle
1.
Patients will be asked to provide consent for access archived tumour tissue and blood samples where
possible to allow for potential future biomarker and pharmacodynamics assessment.
Inclusion/Exclusion Criteria
The study will enroll patients with locally advanced or metastatic Non-Small Cell Lung Cancer
(NSCLC) after failure of at least one prior chemotherapeutic regimen.
Inclusion Criteria:

Diagnosis of Stage IIIB or Stage IV adenocarcinoma of the lung. Patients with mixed
histology will be eligible if adenocarcinoma is the predominant histology.

Prior chemotherapy for relapsed or metastatic NSCLC.

Measurable disease according to RECIST version 1.1.

Age≥18years.

Life expectancy of at least 3 months.

Negative human chorionic gonadotropin (hCG) test in women of childbearing potential
(defined as women ≤ 50 years of age or history of amenorrhea for ≤ 12 months prior to study
screening).  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 1 month after the final administration of VAL401.  Note that female patients may be
surgically sterile (with appropriate documentation in the patient’s medical records).

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.

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.


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Exclusion Criteria:

Radiotherapy or surgery (other than biopsy) within 4 weeks prior to Cycle 1 Day 1.

Any chemotherapy regimens (including investigational agents) with delayed toxicity with 6
weeks of Cycle 1 Day 1, or received any chemotherapy regimens given continuously or on a
weekly basis which have limited potential for delayed toxicity within 2 weeks prior to Cycle 1
Day 1.  Palliative treatment regimens, and other concomitant drugs regimens are permitted
with stable toxicity, and recording of all concomitant medications (including herbal).

Pregnant or lactating female patients.

Active hepatitis B or C or other active liver disease (other than malignancy).

Any active, clinically significant, viral, bacterial, or systemic fungal infection within 2 weeks
prior to Cycle 1 Day 1; other than CMV which may be present providing any required
concomitant anti-viral treatment is recorded appropriately.

Known human immunodeficiency virus positivity.

History of clinically significant cardiac condition, including ischemic cardiac event,
myocardial infarction or unstable cardiac disease with 3 months prior to Cycle 1 Day 1.

Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or
requiring treatment with anticonvulsants or steroids and/or leptomeningeal disease).

Any known contraindications to Risperidone or patients who would not be eligible to receive
the treatment as defined in the Special Warnings and Precautions section of the local label for
Risperidone.

Any medical history that in the Investigator’s opinion would jeopardise compliance with the
protocol.
Route of Administration, Dose Schedule and Duration
VAL401 is administered as an oral capsule, each capsule containing either 5 mg or 1 mg of active
ingredient.  The starting dose level of VAL401 is 2 mg as a single daily dose on Cycle 1 Day 1, with
escalation of 2 mg per day to a maximum of 10 mg per day such that Cycle 1 Day 2 provides 4 mg
VAL401 as a single daily dose, Day 3: 6 mg, Day 4: 8 mg, Day 5 and all subsequent days 10 mg as a
single daily dose.  The dose levels assessed in this study i.e. the dose and the dosing administration
schedules, may be adjusted following the study dose escalation rules, based on review of on-going
evaluation generated during the study.
The majority of VAL401 doses will be self-administered by the patient at home, with the investigator
supplying sufficient capsules to the patient at each visit to maintain dosing until the next site visit.
Statistical Methods
Results will be presented using descriptive statistics. Data collected at screening and up to and
including the Pharmacokinetic measurements collected on Day 15 Cycle 1 will be analysed during a
preliminary analysis point when all patients have reached this stage.  Final analysis will correlate all
remaining data with the preliminary set after last patient, last visit and complete data lock.
All patients who receive at least one dose of VAL401 will be included in the safety analysis.  Patients
who fail to receive one full cycle of VAL401 therapy, for reasons other than DLT, may be replaced.


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Schedule of Study Assessments
Assessment
Screening
Cycle 1
Subsequent Cycles
(28 days each)
Final
Study
Visit8
Day
Day
Day -28 to 0
1
2
3
4
5
6
to
14
15
16
to
28
1
2
to
14
15
16
to
28
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
Vital signs2
X
X
X
X
X
X
X
X
X
X
ECG (resting 12-
lead)3
X
X
X
X
X
X
X
X
X
X
Clinical chemistry*
X
X
X
X
X
X
Haematology
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
Urinalysis*
X
X
X
X
Tumour assessment4
X
Perform after every 3 cycles +/- 1 week
X
Biomarker testing5
(X)
Adverse events
X
X
X
X
X
X
X
X
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
VAL401
administration
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics6
X
X
HRQoL7
X
X
X
X
X
X
Footnotes - General

Assessments made on Day 1 of each cycle are to be conducted prior to VAL401 administration, unless
specified otherwise.

Additional assessments may be conducted as clinically indicated.

(X) denotes optional.

A tolerance of +/-1 day will be permitted for all study visits after completion of the dose escalation period
and a tolerance of -1 day for all assessments relative to the study visit, unless specified otherwise.
*
safety bloods will include HBV, HCV, HIV, CMV IgG IgM testing at Screening; female patients 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 drug administration on Day 1 of each cycle; Symptom-directed physical
examination is acceptable at other time-points. Weight will be recorded at Screening, on Day 1
of each cycle and at the Final Study Visit.
2
On Cycle 1, Day 1 vital signs (heart rate, BP, axillary temperature and respiration rate) will be
assessed pre-dose and up to 1 hour after the VAL401 administration.  On all other visit days during
each cycle, vital signs will be assessed pre-dose only.


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3
On Cycle 1, Day 1 a resting 12-lead ECG will be conducted pre-dose and up to 1 hour after the
VAL401 administration. On all other visit days during each cycle, vital signs and 12-lead ECG
will be assessed pre-dose only.   Each assessment must be taken in triplicate at these time points.
4
CT or MRI performed at Screening and after every 3 cycles of treatment (+/- 1 week).  Additional
scans may be performed to confirm a Response or disease progression as appropriate for response
assessment guidelines.  Any requirement for confirmatory scans will typically be performed at
the next protocolled assessment time point.  Other informative markers may be taken as
appropriate. Patients remaining on study after 6 cycles will have tumour assessment every 3-6
cycles.
5
Patients will be asked to give consent to perform future biomarker testing of archived and/or fresh
tumour tissue where sample is available.  Consenting patients will also have a 10 mL blood
sample taken for preparation of a germ-line DNA sample at screening (recommended time-point
only) for biomarker assessment.
6
PK sampling will be conducted at Cycle 1 at the following sample times.  Two PK profiles may
be taken (Day 1 and Day 15): each will not exceed up to 10 samples (taken up to 24 hours post
drug administration; see example time points below).    The actual time for each blood draw must
be accurately recorded. Cycle 1, Day 15 measurement should be taken after between 7 and 14
days of continuous treatment.

Cycle1, Day 1: pre-dose (0h) then 10, 15, 30 min, 1, 2, 4, 8, 10 and 24 h post-
administration.

Cycle 1, Day 15: pre-dose (0h) then 10, 15, 30 min, 1, 2, 4, 8, 10 and 24 h post-
administration.
7
HRQoL survey EORTC QLQ – C30 version 3 will be required to be completed by the patient at
the fortnightly site visits, at Screening and at the Final Visit.
8
The Final Study Visit should be performed 30 +/-3 days after the last dose of VAL401 to enable
a final safety assessment.


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TABLE OF CONTENTS
LIST OF ABBREVIATIONS
15
1
INTRODUCTION
17
1.1
Non-small cell lung cancer
17
1.2
Rationale for Treatment with VAL401 in non-small cell lung cancer
19
1.3
Summary of non-clinical development
19
1.4
Clinical Evaluation of VAL401
20
1.5
Rationale for Dose Selection
20
1.6
Safety Guidance for Investigators
21
2
STUDY OBJECTIVES
22
3
SELECTION CRITERIA
23
3.1
Inclusion Criteria
23
3.2
Exclusion Criteria
23
3.3
Patient Withdrawal or Discontinuation
24
3.4
Replacement of Withdrawn Patients
24
3.5
Procedures for Discontinuation
24
3.6
Study or Site termination
24
4
INVESTIGATIONAL PLAN
26
4.1
Study Design
26
4.2
Dose Escalation Scheme and DLT Evaluation
27
4.2.1
Dose Escalation
27
4.2.2
Dose Limiting Toxicity
27
4.3
Dose Adjustments or Delays
28
4.4
Dose Reduction
28
5
STUDY SCHEDULE
29
5.1
Schedule of Study Assessments
29
5.2
Volume of Blood Sampling
32
5.3
Description of Study Assessments
33
5.3.1
Adverse Events
33
5.3.2
Laboratory Safety Measurements
33
5.3.3
Resting 12-lead electrocardiogram (ECG)
33


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5.3.4
Vital Signs
34
5.3.5
Pharmacokinetic assessments
34
5.3.6
Tumour Assessment
34
5.3.7
Biomarker testing
35
6
STUDY MEDICATION AND ADMINISTRATION
36
6.1
Study Medication
36
6.2
Selection of Doses in the Study and Duration of Treatment
36
6.3
Packaging and Labelling
36
6.4
VAL401 Administration
36
6.5
Storage
37
6.6
Replacement of Medication
37
6.7
Accountability
37
6.8
Treatment Allocation
38
6.9
Blinding and Procedures for Un-Blinding the Study
38
6.10
Permitted and Restricted Concomitant Medications/Treatments
38
7
ADVERSE EVENTS AND REPORTING REQUIREMENTS
39
7.1
Assessment of Safety
39
7.2
Adverse Event Definition
39
7.3
Importance of Adverse Event Reporting
39
7.4
Evaluating Adverse Events
40
7.4.1
Severity
40
7.4.2
Seriousness
40
7.4.3
Pregnancy
41
7.4.4
Misuse and Overdose
41
7.4.5
Investigation Product Complaints
42
7.4.6
Relationship
42
7.5
Evaluating Dose Limiting Toxicities (DLTs) / Serious Adverse Events (SAEs)
43
7.5.1
Unexpected adverse events
43
7.6
Reporting DLTs / SAEs
43
7.6.1
Reporting SAEs to the IRB or Ethics Committee and Regulatory Authorities
43
7.6.2
Follow-up information on an SAE
44


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8
DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES
45
8.1
End of Study and Study Completion
45
8.2
Statistical Considerations
45
8.3
Demographic and Other Baseline Characteristics
45
8.4
Statistical Methods for Safety Parameters
45
8.5
Statistical Methods for Pharmacokinetic Parameters
46
8.6
Evaluation of Tumour Response
46
8.7
Estimated Sample Size
46
9
QUALITY ASSURANCE
47
9.1
Data Recording
47
9.2
Study Monitoring
47
9.3
Clinical Study Audit
47
9.4
Clinical Study Report
47
9.5
Data Retention and Availability
47
10
ETHICS REVIEW / INFORMED CONSENT
48
10.1
Ethical Conduct of the Study
48
10.2
Informed Consent
48
10.3
Insurance
49
11
PUBLICATION POLICY
50
REFERENCES
51
A.A
APPENDIX A: ECOG PERFORMACE STATUS
52
A.B
APPENDIX B: NCI CTCAE v4.03
53
A.C
APPENDIX C: LOCAL LABORATORY PARAMETERS
54


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LIST OF ABBREVIATIONS
ADC
Adenocarcinoma
AE
Adverse Event
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC
Area under curve
BP
Blood Pressue
BRAF
Gene for which mutations are associated with lung cancer
BSA
Body Surface Area
CI
Confidence Interval
Cmax
Maximum serum concentration
Cmin
Minimum serum concentration
CNS
Central Nervous System
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computerised tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DNA
De-oxy ribose nucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Co-operative Oncology Group
EGFR
Gene for which mutations are associated with lung cancer
EORTC
European Organisation for Research and Treatment of Cancer
ESMO
European Society for Medical Oncology
FDA
Food and Drug Administration
FFPE
Formalin fixed Parafin embedded
GCP
Good Clinical Practice
h
hour
HBV
Hepatitis B virus
hCG
human Chorionic Gonadotropin
HCV
Hepatitis C virus
HER2
Gene for which mutations are associated with lung cancer
HRQoL
Health Related Qulaity of Life
HSD10
Hydroxysteroid dehydrogenase type 10
ICH
International Conference of the Harmonisation of Technical Requirements for Medicinal Products for Human Use
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Investigational Review Board
kg
kilogram
MAD
Maximum Administered Dose
mg
milligram
min
minute
mL
millilitre
mm
millimetre
MRI
Magnetic Resonance Imaging


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MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NOAEL
No Adverse Effect Level
NSCLC
Non-small cell lung cancer
PFS
Progression-free Survival
PGMC
Propylene Glycol Monocaprylate
PK
Pharmacokinetics
pRBC
packed Red Blood Cells
PS
Performance Status
RECIST1.1
Response Evaluation Criteria in Solid Tumours
RET
Gene for which mutations are associated with lung cancer
RFA
Radiofrequency ablation
ROSI
Gene for which mutations are associated with lung cancer
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCC
Squamous cell carcinoma
sec
second
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SmPC
Summary of Product Characteristics
TKI
Tyrosine Kinase Inhibitors
WHO
World Health Organisation


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1
INTRODUCTION
VAL401 is an equimolar mixture of Risperidone (active) and Rumenic Acid (excipient) in a liquid
lipid filled capsule formulation that is under development by ValiSeek Limited, UK for the use as a
therapy in the treatment of non-small cell lung cancer (adenocarcinoma).
1.1
Non-small cell lung cancer
Approximately one third of all cancer-related deaths are due to lung cancer, which accounts for more
deaths each year than breast, prostate and colon cancer combined (Schiller et al., 2002). Whereas lung
cancer in men peaked in the late 1980’s, with a rate of over 50/100,000 men and falling by about a
third thereafter to about 36/100,000 men, the rate in EU women has been growing over the past two
decades. Causative factors of lung cancer are smoking, which is the main cause, responsible for more
than 80% of cases, and there are also certain occupational factors such as exposure to asbestos,
polycyclic aromatic hydrocarbons, crystalline silica and diesel exhaust. In fact, in 2012 diesel exhaust
was classified as a type 1 carcinogen by the International Agency for Research against Cancer in
Lyon, France (Sculier, 2013).
NSCLC is defined as a cancer of the lung which is not of the small cell carcinoma (oat cell
carcinoma) type. The term "non-small cell lung cancer" applies to the various types of bronchogenic
carcinomas (those arising from the lining of the bronchi). The World Health Organization (WHO)
identifies multiple forms of NSCLC, but the major forms are squamous cell carcinomas (SCCs),
adenocarcinoma (ADC) and large-cell (undifferentiated) carcinoma (Gazdar, 2010).
NSCLC accounts for 80-85% of all lung cancer cases (D’Addario, 2010). Approximately 90% of lung
cancers among men and 80% among women are related to smoking. The majority of patients present
with advanced disease. There is a considerable difference in the incidence across the different
countries in Europe, with rates varying from 22 to 63% per 100,000 in men and from 5 to 33 per
100,000 per year in women, respectively.
The median survival of patients with untreated metastatic NSCLC is only about 4-5 months, with a
survival rate at one year of about 10% (Schiller, 2002).
Symptoms of NSCLC
Lung cancer is often insidious, producing no symptoms until the disease is well advanced. In
approximately 7-10% of cases, lung cancer is diagnosed in asymptomatic patients when a chest
radiograph performed for other reasons reveals the disease. At initial diagnosis, 20% of patients have
localized disease, 25% of patients have regional metastasis, and 55% of patients have distant spread of
disease.
Signs and symptoms of lung cancers may be due to the primary tumour, locoregional spread,
metastatic disease, or ectopic hormone production. Cough is reported to be the most common
presenting symptom of lung cancer. Other respiratory symptoms include dyspnoea, chest pain, and
haemoptysis. Haemoptysis has been described as the one symptom often prompting more rapid
presentation (Corner, 2005).


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Diagnosis of NSCLC
According to the ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up,
pathological diagnosis should generally be made according to the World Health Organisation (WHO)
classification (Reck, 2014). Genetic alterations have been identified in many small subsets of NSCLC,
such as ROSI, HER2, BRAF and RET alterations. Activating (sensitising) epidermal growth factor
(EGFR) mutations are predictive for response to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib,
erltinib, and afatinib.
Standard tests for diagnosis include (after a complete history including smoking history and
comorbidities, weight loss, performance status (PS) and physical examination) routine haematology,
renal and hepatic function and bone biochemistry. Contrast-enhanced computed tomography (CT)
scan of the chest and upper abdomen should be carried out. Dependent on the outcome, other imaging
is conducted to determine potential CNS involvement and metastatic disease.
Treatment of NSCLC
Treatment depends upon the stage of the disease.
Stage I
Non-small cell lung cancer can often be removed with surgery. If there are other medical problems, or
if the patient is not fit enough to have surgery, then radiotherapy may be given instead.
Chemotherapy is sometimes used after surgery (adjuvant chemotherapy) or before surgery and/or
radiotherapy (neo-adjuvant).
Occasionally, radiofrequency ablation (RFA) may be used if other treatments are not suitable.
Stage II
It may be possible to remove stage 2 non-small cell lung cancer with surgery. Radiotherapy may be
used for people who are not fit enough for surgery or choose not to have it. Chemotherapy is often given
following surgery or radiotherapy.
Stage III
Non-small cell lung cancer can sometimes be removed with surgery, although this often is not possible
if the cancer has metastasized. Neo-adjuvant or adjuvant chemotherapy may be given.
Stage IV
Chemotherapy should be offered to patients with stage IV NSCLC and good performance status to
improve survival, disease control and quality of life. Chemotherapy for advanced NSCLC should be a
combination of a single third generation drug (docetaxel, gemcitabine, paclitaxel or vinorelbine) plus
a platinum drug. Either carboplatin or cisplatin may be administered, taking account of their toxicities,
efficacy and convenience. Patients who are unable to tolerate a platinum combination may be offered
single-agent chemotherapy with a third-generation drug. Docetaxel monotherapy should be
considered if second-line treatment is appropriate for patients with locally advanced or metastatic
NSCLC in whom relapse has occurred after previous chemotherapy.
A significant advance in therapy has been made with the introduction of tyrosine kinase inhibitors
(TKIs) for the treatment of NSCLC with activating mutation of the EGFR gene (targeted therapy).
Chemotherapy and TKIs have no cross-resistance and hence administration of TKI has the same effect
on overall survival whether administered as first-line or salvage treatment (Sculier, 2013).


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1.2
Rationale for Treatment with VAL401 in non-small cell lung cancer
HSD10 is an enzyme which plays a protective role in stressed cells – with particular up-regulation
under nutrient-limiting conditions such as those found in cancer (Carlson, 2015).  This up-regulation
in many cancers, in particular those with a hormone-driven growth factor such as adenocarcinomas,
has long been described, and although HSD10 has been proposed as a druggable target (Carlson 2015,
Kissinger, 2004), it is thus far unexploited, and no current cancer treatments have been designed to
target HSD10.
HSD10 is predominantly mitochondrial in location in healthy cells, but under stressed conditions,
migration to the mitochondrial membrane is observed, allowing access from the cytoplasm of the cell.
This allows for a targeting mechanism in which the enzyme is accessible by many drugs only in
cancerous (or similarly stressed) cells, and does not negatively affect healthy cell growth (Carlson,
2015).
During an enzyme assay screening process of a number of related drugs, Risperidone was selected as
having substantial inhibitory activity on HSD10 both in oxidative and reductive functions of the
enzyme.
In in vitro assays, Risperidone alone was found to have insufficient activity against the growth of
cancer cells, but in formulation with the lipid excipient Rumenic Acid, biologically relevant activity
against several adenocarcinoma cell lines (including those representing non-small cell lung cancer,
small cell lung cancer, breast cancer, pancreatic cancer and prostate cancer) was observed and seen to
be specific to adenocarcinoma cell lines. Rumenic Acid alone has no effect on the growth of cancer
cell lines in our in vitro assays.
VAL401 is a formulation of Risperidone in a lipid filled capsule, with the lipid excipient containing
the required Rumenic Acid component.
Subsequent in vivo assays confirmed the activity in non-small cell lung cancer with oral
administration of VAL401 demonstrating a reduction in tumour growth rates in mice.
Both in vitro and in vivo studies have found that this unique formulation enables the anti-cancer
activity of Risperidone to be accessed in a simple oral formulation.  ValiSeek have chosen to advance
VAL401 in Non-small Cell Lung cancer as a primary indication, where there is a high unmet medical
need.
1.3
Summary of non-clinical development
VAL401 has been evaluated in both single and repeat dose toxicity studies in rats in which VAL401
was administered orally daily for up to one month at doses of 10 mg/kg/day – this is greater than an
order of magnitude above the maximum dosage intended in this study (10 mg/day).  These studies
concluded the minimum NOAEL to be the maximum level tested (10 mg/kg/day), and demonstrated
no effects beyond those predicted with the use of Risperidone.
Pharmacokinetic analysis in rats both in acute and chronic treatment demonstrated exposure to
Risperidone in VAL401 to be comparable to that exposure reported for conventional Risperidone


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formulations, concluding that the effects and toxicity are abridged and current guidelines for safety
and tolerability will be used as an indicative starting point for this study.
Full details of the non-clinical pharmacology and toxicology programs for VAL401 can be found in
the latest edition of the Investigator’s Brochure.
1.4
Clinical Evaluation of VAL401
VAL401 has not been administered to humans before, although the API Risperidone has been
administered in alternative formulations. This study is proposed using the safety and tolerability of
the clinical API, Risperidone as a guideline, and the safety guidelines detailed in the SmPC for
Risperidone should be considered integral to this protocol.
1.5
Rationale for Dose Selection
A NOAEL for VAL401 has been defined as a minimum of 10 mg/kg.
Allometric scaling employed to relate rat dose to human equivalent dose:
Conversion
Conversion
factor
Rat dose
Human
equivalent
70 kg
Human
patient
Margin over
proposed
maximum dose
b= 0.67*
0.156
10 mg/kg
1.56 mg/kg
109 mg/day
10
b=0.75
0.245
10 mg/kg
2.45 mg/kg
171 mg/day
17
*Use of the conversion factor 0.67 is the preferred approach for first in human studies by the FDA
Conversion of the dose ranges tested in the xenograft efficacy studies translates to an approximate
maximum 10 mg per day (based on a calculation from a mouse 2mg/kg/day using a BSA calculation).
Risperidone is currently licensed for use as an anti-psychotic at up to 16 mg maximum dose per day,
although prescription is more commonly between 4 and 8 mg dose per day, due to a clinically proven
lack of greater anti-psychotic activity above 8 mg per day in the majority of patients.
By ensuring that our intended dosing regimen is within the current licensed use, VAL401 safety and
tolerability can be confidently predicted.
Risperidone in conventional formulation is typically subjected to an initial dose escalation schedule
with a ramping of daily dose from 2 mg to the required dose for efficacy at 24 hour intervals.
VAL401 is proposed to follow a comparable dose initiation schedule, with the starting dose of 2
mg/day, recommended to be taken in the evening to minimise quality of life effects of the temporary
sedative effect of Risperidone, with a daily escalation in 2 mg increments to a maximum of 10 mg per
day, or MTD if this is found to be lower for an individual patient.
The dose escalation and maintenance procedure in conjunction with close clinical monitoring and
medical supervision is considered appropriate for the IMP under consideration.


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1.6
Safety Guidance for Investigators
Investigators should refer to the latest edition of the IB for a full review of the potential risks
associated with VAL401 and details of expected adverse events. The SmPC for Risperidone should
be considered alongside the IB and this protocol, as adverse events associated with Risperidone usage
can be expected to also occur with VAL401 usage.


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2
STUDY OBJECTIVES
The objectives of this study are to assess the safety, tolerability, pharmacokinetics (PK) and efficacy
of VAL401 in patients with locally advanced or metastatic non-small cell lung cancer.
Objective
Endpoint
Primary:

Progression-free survival (PFS)

As assessed by RECIST 1.1 criteria. PFS
will be defined as the time from
randomisation to disease progression (or
death if the patient died before
progression)
Secondary:

To evaluate the pharmacokinetics of
VAL401

To assess potential disease
modifying activity

To determine the safety and
tolerability of VAL401

To evaluate patient quality of life
during VAL401 treatment

Overall Survival

Assessment of pharmacokinetic variables
in collected blood samples (including Cmax,
Cmin, AUC) on Day 1 and Day 15 of Cycle
1.

Objective tumour response rates according
to RECIST 1.1 including time to objective
response and duration of objective
response; or disease control (defined as a
patient with objective response or stable
disease) according to RECIST version 1.1
including duration of disease control

Ongoing evaluation of AEs during
treatment and follow up

Changes in patient quality of life measured
by HRQoL assessment EORTC QLQ –
C30 provided in Georgian under license
from EORTC
Exploratory:

Biomarker testing

Testing of germline DNA in single blood
sample at Day 0 for biomarker assessment.
Testing of historic tumour biopsy material
where available.


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3
SELECTION CRITERIA
The study will enroll patients with locally advanced or metastatic Non-Small Cell Lung Cancer
(NSCLC) after failure of at least one prior chemotherapeutic regimen.
3.1
Inclusion Criteria

Diagnosis of Stage IIIB or Stage IV adenocarcinoma of the lung. Patients with mixed
histology will be eligible if adenocarcinoma is the predominant histology.

Prior chemotherapy for relapsed or metastatic NSCLC.

Measurable disease according to RECIST version 1.1.

Age≥18years.

Life expectancy of at least 3 months.

Negative human chorionic gonadotropin (hCG) test in women of childbearing potential
(defined as women ≤ 50 years of age or history of amenorrhea for ≤ 12 months prior to study
screening).  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 1 month after the final administration of VAL401.  Note that female patients may be
surgically sterile (with appropriate documentation in the patient’s medical records).

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.

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.
3.2
Exclusion Criteria

Radiotherapy or surgery (other than biopsy) within 4 weeks prior to Cycle 1 Day 1.

Any chemotherapy regimens (including investigational agents) with delayed toxicity with 6
weeks of Cycle 1 Day 1, or received any chemotherapy regimens given continuously or on a
weekly basis which have limited potential for delayed toxicity within 2 weeks prior to Cycle 1
Day 1.  Palliative treatment regimens, and other concomitant drugs regimens are permitted
with stable toxicity, and recording of all concomitant medications (including herbal).

Pregnant or lactating female patients.

Active hepatitis B or C or other active liver disease (other than malignancy).

Any active, clinically significant, viral, bacterial, or systemic fungal infection within 2 weeks
prior to Cycle 1 Day 1; other than CMV which may be present providing any required
concomitant anti-viral treatment is recorded appropriately.

Known human immunodeficiency virus positivity.

History of clinically significant cardiac condition, including ischemic cardiac event,
myocardial infarction or unstable cardiac disease with 3 months prior to Cycle 1 Day 1.

Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or requiring
treatment with anticonvulsants or steroids and/or leptomeningeal disease).

Any known contraindications to Risperidone or patients who would not be eligible to receive
the treatment as defined in the Special Warnings and Precautions section of the local label for
Risperidone.

Any medical history that in the Investigator’s opinion would jeopardise compliance with the
protocol.


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3.3
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
VAL401 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.  Patients may be replaced if they withdraw prior to completion of Cycle 1,
unless the reason for withdrawal is a toxicity related to treatment with VAL401, in order to evaluate
tolerability and possible DLT.  Example reasons for discontinuing a patient from this study are:

Disease progression.

The patient experiences a toxicity, where the re-introduction of VAL401 (including a dose
reduction of VAL401), is not considered suitable.  Exceptions may be considered where the
toxicity is not considered to be VAL401 treatment-related.

Other toxicities or events, unrelated to VAL401, 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.
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 VAL401 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 may involve an
adjustment (de-escalation) in dose or dose schedule.
3.4
Replacement of Withdrawn Patients
If a patient is withdrawn from the study for reasons other than a DLT-associated event before the end
of the first treatment cycle during the dose escalation portion of the study, the patient will be replaced.
Patients who withdraw from the study or discontinue treatment after completion of the first treatment
cycle will not be replaced.
3.5
Procedures for Discontinuation
If a patient withdraws from the study prior to completion of Cycle 6, the reason for withdrawal should
be sought and recorded in the patient file and the Case Report Form (CRF).  Every effort will be made
to complete the Final Study Visit.
3.6
Study or Site Termination
If the Sponsor or their representatives, Investigator, or Competent Authority officials discover
conditions during the study that indicate that the study or site involvement should be terminated, this
action may be taken after appropriate consultation with the Sponsor and the Investigator.  Conditions
that may warrant termination of the study or involvement of a study site include, but are not limited
to:

The discovery of an unexpected, serious, unacceptable risk to patients enrolled in the study.

The  decision  on  the  part  of  the  Sponsor  to  suspend  or  discontinue  testing, evaluation,
or development of the study drug.

Failure of the Investigator(s) to comply with pertinent clinical trial regulations.


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
Submission  of  knowingly  false  information  from  the  research  facility  to  the Sponsor,
study monitor, or Competent Authority.

Insufficient adherence to protocol requirements.
Study termination and follow-up will be performed in accordance with applicable local regulations.


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4
INVESTIGATIONAL PLAN
4.1
Study Design
This is a Phase II, open label study to assess the efficacy, safety and tolerability of VAL401 in the
treatment of patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) after
failure of at least one prior chemotherapeutic regimen. Eligible patients will be enrolled as a single
cohort and treated with VAL401, given as oral capsules.
Each patient will be dosed in 28 day cycles according to the schedule of: Cycle 1 Day 1: 2 mg in a
single daily dose; Cycle 1 Day 2: 4 mg in a single daily dose; Cycle 1 Day 3: 6 mg in a single daily
dose; Cycle 1 Day 4: 8 mg in a single daily dose; Cycle 1 Day 5 and onwards: 10 mg in a single daily
dose. Cycles 2 – 6 each patient will receive a single daily dose of 10 mg (or their personal MTD if
established).
If a patient experiences a DLT, the dose will be reduced to the previous acceptable dose, and the
patient will remain on this personal MTD for the remainder of the study.
VAL401 is supplied as 5 mg and 1 mg dose capsules, each day’s individual dose composed of the
relevant combination of 1 mg and 5 mg capsules to total the required level.
All patients will remain on 10 mg as a single daily dose (or their personal MTD if reached) until they
experience disease progression or unacceptable toxicity or until completion of 6 x 28 days cycles.
Patients will visit the study sites on each dosing day during the dose escalation period of Cycle 1 and
then fortnightly at a minimum for a physical examination, recording of AEs and monitoring of quality
of life by HRQoL questionnaires.   Laboratory screens will be assessed at visits as indicated in the
schedule, being Cycle 1 Day 5 (final day of dose escalation), Day 15 of all Cycles, Day 1 of Cycles 2
– 6 and at the Screening visit.
Tumour assessment, including imaging (CT scan or other appropriate
scan) where relevant, will be assessed in all patients at Screening and after every 3 cycles of
treatment.  Follow up assessments during the main study (Cycle 1-6) will be conducted in accordance
with RECIST 1.1 (Eisenhauer 2009).
The majority of VAL401 doses will be self-administered by the patient at home, with the investigator
supplying sufficient capsules to the patient at each visit to maintain dosing until the next site visit.
The Investigator must stress to the patient the importance of reporting any deviations from protocol
during home-dosing and encourage the patient to immediately report any potential AEs to the
Investigator even if a visit is not due.
A full PK profile will be taken after the first dose of VAL401 and on Cycle 1 Day 15.
Patients will be asked to provide consent for access to archived tumour tissue, and blood samples and
fresh biopsies will be taken (where possible) to allow for potential biomarker and PD assessment.
Patients whose disease has not progressed and who have not been withdrawn from therapy due to
toxicity are eligible to continue receiving additional cycles of VAL401.   For the purposes of this
study, a full treatment course of VAL401 will considered to be 6 cycles.   However, patients who
respond to VAL401 treatment during the trial may have extended treatment with the Investigational
Medicinal Product (IMP) where recommended by the investigator.  Such patients will continue to be
followed up for safety and continued response (see Schedule of Study Assessments).   Patients
receiving treatment beyond Cycle 6 may continue to be treated and followed up as part of this
protocol, or be transferred to an extended treatment protocol.


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4.2
Dose Escalation Scheme and DLT Evaluation
4.2.1
Dose Escalation
During Cycle 1 of treatment the following escalation steps are recommended in the absence of
VAL401-related events which would lead to a more cautious dose escalation:
Cycle 1; Day
Daily Dose
Capsules administered
1
2 mg
2 x 1 mg
2
4 mg
4 x 1 mg
3
6 mg
1 x 5 mg + 1 x 1 mg
4
8 mg
1 x 5 mg + 3 x 1 mg
5 and subsequent
10 mg
2 x 5 mg
In the case where a potentially significant toxicity which is not a DLT, or a trend in toxicities seen,
considered to be related to treatment with VAL401 occur and are considered to be a precursor of a
clinically significant toxicity event; subsequent dose escalation steps in that patient may be more
conservative (1mg per day increase until MTD reached, or a 24 hour delay until the next dose increase
– at the discretion of the Investigator).  This restriction may be reversed where there is no suggestion
of a potentially clinical significant toxicity in the subsequent dose level.
Where a patient establishes a DLT, the dose should be reduced by one step, and the patient continued
on this dose for the remainder of the study providing that the DLT has been resolved.  This dose will
be noted as the patient’s personal MTD. The Schema below details the process for dose escalation
decisions.


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4.2.2
Dose Limiting Toxicity
The maximum feasible dose which may be administered is 10 mg per day.  Should this dose be
reached without the need to de-escalate the dose due to DLT, it will be termed the Maximum
Administered Dose (MAD).
Safety Evaluations will be conducted daily during the dose escalation period (a minimum of Day 1 –
Day 5 of Cycle 1), weekly for the remainder of cycle 1, and fortnightly thereafter.  All events and
suspected DLTs will be graded according to the Common Terminology Criteria for Adverse Events
(CTCAE) version 4.03.
A DLT is defined as a VAL401-related Grade 3 or 4 adverse event that, in the opinion of the
Investigator represents a clinically significant hazard to the subject, with the following exceptions as
considered appropriate:

Grade 3 or 4 laboratory abnormalities, which resolve spontaneously or can be corrected with
appropriate treatment (such as electrolytes).  For example, an event returns to baseline or to
Grade 1 at the next assessment.

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.
Qualifying toxicity events must be considered to be clinically relevant e.g. in duration, and likely to
be related to treatment with VAL401.  DLT events will also be considered in terms of what is
considered to be an appropriate next escalation step: in the case where the Investigator considers a
daily escalation of 1 mg instead of 2 mg per day in the dose escalation period of Cycle 1, the toxicity
of concern should be declared a DLT.
4.3
Dose Adjustments or Delays
In the case where a potentially significant toxicity which is not a DLT, or a trend in toxicities seen,
considered to be related to treatment with VAL401 occur and are considered to be a precursor of a
clinically significant toxicity event; subsequent dose escalation steps in that patient may be more
conservative (1mg per day increase until MTD reached, or a 24 hour delay until the next dose increase
– at the discretion of the Investigator).  This restriction may be reversed where there is no suggestion
of a potentially clinical significant toxicity in the subsequent dose level.
In the case where a DLT is observed the dose should be reduced to a prior acceptable level and
maintained at that level providing that the DLT resolves.  After resolution of the DLT the Investigator
may propose a further increase in dose if they have reason to believe the patient would benefit from a
slower dose escalation to provide an eventual higher MTD.  Any attempted dose increase in this
scenario is at the discretion of the Investigator and noted on the CRF.
If a dose is missed the patient should take the next dose on schedule and should not try to catch up the
missed dose by taking double.  If two or more consecutive doses are missed, the patient must re-
escalate to their MTD, starting again at 2 mg per day.
4.4
Dose Reduction
The Sponsor may advise on a dose reduction step based on safety and on-going data evaluation from
early enrolled patients.  Intra-patient dose reduction of VAL401 is also permitted in this study.
Investigators may choose to administer a lower dose which has previously been assessed during the


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trial (or intermediate dose), to an individual patient based on safety evaluation of either the individual
patient or other patients in the study.
Note that this approval may be expedited at any time if the Sponsor or Investigator receive
information that is pertinent to patient welfare.  All intra-patient dose reductions must be justified in
writing as a preferable option over patient withdrawal.


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5
STUDY SCHEDULE
Patients will attend the clinic for Screening assessments up to 28 days before receiving the first dose
of VAL401.
Patients will be closely monitored after receiving their first dose of VAL401 and remain in the
hospital clinic overnight for observation until the final PK sample is taken 24 hours after the initial
dose; the second dose is administered, and all Day 2 study assessments have been completed. The
study will commence with a dosing schedule of VAL401 given orally as a capsule (or combination of
capsules) according to the dose escalation in Cycle 1 and then all on all days of a four week cycle.
The majority of VAL401 doses will be self-administered by the patient at home, with the investigator
supplying sufficient capsules to the patient at each visit to maintain dosing until the next site visit.
A tolerance of +/-1 day will be permissible for all study visits, except the dose escalation Cycle 1
visits which have no tolerance permitted and except the final study visit, which will have a tolerance
of +/-3 days (this does not take into account any required dose delays).  A tolerance of -1 day is
permitted for all assessments relative to the study visit, unless specified otherwise (see footnotes to
Schedule of Study Assessments).
Additional assessments may be conducted as clinically indicated.
5.1
Schedule of Study Assessments
Please also refer to the Schedule of Study Assessments tables and their associated footnotes.  Below is
a summary of study assessments described by visit.
Cycle 1, Screening (up to 28 days prior to Cycle 1, Day 1)

Informed consent (includes consent to obtain archived biopsy sample and for fresh biopsy
samples where possible)

Demographics

Medical history (including tumour biomarker characteristics if known – for example EGFR
mutant)

Concomitant medication

Inclusion/exclusion checks

ECOG Performance Status

Full physical examination (including height and weight)

Vital signs

ECG (resting 12-lead)

Clinical Chemistry

Haematology

Coagulation

Urinalysis

Virology to test for HBV, HCV, HIV, CMV IgG IgM

Serum pregnancy test (if applicable)

Tumour assessment (include historical information and Screening scans)

Biomarker testing – blood sample to obtain germ-line DNA

Health-related Quality of Life Questionnaire
Cycle 1, Day 1

Full physical examination

Vital signs (pre-dose and after VAL401 administration)


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
ECG (resting 12-lead) (taken in triplicate; pre-dose and up to 1 hour after VAL401
administration)

Urinalysis (include urine pregnancy test if applicable; no need to retest if within 7 days of last
evaluation)

Adverse events

Concomitant medication

VAL401 administration

PK profile

Health-related Quality of Life Questionnaire
Cycle 1, Day 2

Full physical examination

Vital signs (pre-dose and after VAL401 administration)

ECG (resting 12-lead) (taken in triplicate; pre-dose and up to 1 hour after VAL401
administration)

Adverse events

Concomitant medication

VAL401 administration
Cycle 1, Day 3

Full physical examination

Vital signs (pre-dose and after VAL401 administration)

ECG (resting 12-lead) (taken in triplicate; pre-dose and up to 1 hour after VAL401
administration)

Adverse events

Concomitant medication

VAL401 administration
Cycle 1, Day 4

Full physical examination

Vital signs (pre-dose and after VAL401 administration)

ECG (resting 12-lead) (taken in triplicate; pre-dose and up to 1 hour after VAL401
administration)

Adverse events

Concomitant medication

VAL401 administration
Cycle 1, Day 5

Full physical examination

Vital signs (pre-dose and after VAL401 administration)

ECG (resting 12-lead) (taken in triplicate; pre-dose and up to 1 hour after VAL401
administration)

Adverse events

Concomitant medication

VAL401 administration

Clinical Chemistry

Haematology

Coagulation
Cycle 1, Day 15

Concomitant medication


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
ECOG Performance Status

Full physical examination (including height and weight)

Vital signs

ECG (resting 12-lead)

Adverse events

Clinical Chemistry

Haematology

Coagulation

VAL401 administration

PK profile

Health-related Quality of Life Questionnaire
Cycle 1, Day 29/Cycles 2-6, Day 1

Concomitant medication

ECOG Performance Status

Full physical examination (including height and weight)

Vital signs

ECG (resting 12-lead)

Adverse events

Clinical Chemistry

Haematology

Coagulation

Urinalysis (include urine pregnancy test if applicable)

VAL401 administration

Health-related Quality of Life Questionnaire
Cycles 2-6, Day 15

Concomitant medication

ECOG Performance Status

Full physical examination (including height and weight)

Vital signs

ECG (resting 12-lead)

Adverse events

Clinical Chemistry

Haematology

Coagulation

VAL401 administration

Health-related Quality of Life Questionnaire
Final Study Visit (to be performed 30 days (±3 days) after the last dose of VAL401)

Concomitant medication

ECOG Performance Status

Full physical examination (including height and weight)

Vital signs

ECG (resting 12-lead)

Adverse events

Clinical Chemistry

Haematology

Coagulation

Urinalysis (include urine pregnancy test if applicable)


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
Health-related Quality of Life Questionnaire
Tumour assessment should be carried out after every 3 cycles, at a visit deemed convenient to the
patient and Investigator at any time within the relevant cycle.  If disease progression is suspected,
tumour assessment may be carried out earlier than scheduled.
Where a patient continues VAL401 treatment beyond Cycle 6, the following assessments should be
carried out on the final day of each cycle, and the patient supplied with a full subsequent cycle of
VAL401 capsules:
Cycles 7 and beyond, Day 28

Concomitant medication

ECOG Performance Status

Full physical examination (including height and weight)

Vital signs

ECG (resting 12-lead)

Adverse events

Health-related Quality of Life Questionnaire
5.2
Volume of Blood Sampling
Based on the unit blood volumes given for each study assessment, it is anticipated that patients
enrolled to the dose escalation portion of the study will have a maximum of 420 mL of blood drawn if
they complete all 6 cycles of treatment and the final study visit (including potential for repeat analysis
as clinical required), and have the maximum number of blood samples taken for PK and biomarker
assessment.  Those patients who only complete Cycle 1 plus the final study visit, would have a
maximum of 308 mL blood drawn (including potential for repeat analysis as clinically required).
Duration on trial
Volume of blood drawn
Screening, Cycle 1 and Final Visit
154 mL (assumes maximum samples taken)
Screening, Cycles 1 – 6 and Final Visit
264 mL (assumes maximum samples taken)
Notes
PK – assuming all 20 samples are taken
100 mL
Clinical Chemistry – assuming all 14 samples taken
70 mL
Haematology (including coagulation) – assuming all
14 samples taken
84 mL
Biomarker
10 mL
The volume of blood drawn for each patient will also be described in the Patient Information Sheet.
Efforts will be made to reduce the number of PK samples to be taken upon evaluation of cohort data
during the trial.
5.3
Description of Study Assessments
5.3.1
Adverse Events
Adverse events (AEs) will be captured from the time the patient gives consent until the 30 day follow-
up (Final Study Visit).  There will be a baseline medical condition review taken at screening. AEs,
other than the primary disease under evaluation, that worsen in severity or frequency from this
baseline assessment during the study, should be recorded and reported as AEs.
AEs will be graded according to the NCI CTCAE v4.03 for cancer clinical trials (Appendix B).  For
events not addressed in the CTCAE v4.03, the alternative severity classifications provided in Section


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7.4.1 apply.
AEs should continue to be captured for a further 30 days from the end of the last dose administration
of VAL401.  On-going SAEs will be followed up until considered resolved; returns to baseline; is
chronically ongoing or explained by the Principal Investigator.
Symptoms and signs of exacerbation or worsening of the patient’s primary disease will not be
captured as AEs.  For the purpose of data capture, disease progression as evaluated by RECIST1.1,
will not be considered to be an AE and will be captured in the Tumour Assessment CRF modules.
5.3.2
Laboratory safety measurements
Blood and urine samples for determination of clinical chemistry, haematology, coagulation and
urinalysis parameters will be taken at the times given in the Schedule of Study Assessments and as
clinically indicated.  The date and time of collection will be recorded in the source data and on the
CRF.
Clinical chemistry, haematology, coagulation analysis and urinalysis will be performed at each site’s
local laboratory or other local laboratories as appropriate.   The required blood volume for clinical
chemistry samples is 5 mL and 6 mL for haematology (including coagulation).
Copies of laboratory accreditation certificates and reference ranges will be provided prior to the
analysis of the first patient sample.
The laboratory variables to be measured are described in Appendix C.
5.3.3
Resting 12-lead electrocardiogram (ECG)
For timing of individual measurements refer to Schedule of Study Assessments.
All  12-lead  Electrocardiograms  (ECGs)  should  be  recorded  while  the  patient  is  in  the  supine
position.  ECGs taken on Cycle 1 Days 1 – 5 (the dose escalation period) will be assessed in triplicate
at pre-dose and up to 1 hour after VAL401 administration.  ECGs taken in other site visits may be
taken irrespective of VAL401 timing of dosing. The Investigator or designated physician will review
the paper copies of each of the timed 12-lead ECGs on each of the study days when they are collected.
ECGs will be recorded at 25 mm/sec.  All efforts should be made to ensure that an identical ECG
machine is used to collect traces for individual patients.   If any clinically significant findings are
observed on the ECG, the Investigator will record it as an AE where the finding represents a clinically
significant change from the baseline assessment taken at screening.
5.3.4
Vital signs
For the timing of individual measurements, refer to the Schedule of Study Assessments.  The date and
time of collection and measurement will be recorded on the appropriate CRF.
Measurements of heart rate, axillary temperature, blood pressure and respiratory rate will be made
after the patient has been resting supine for a minimum of 5 minutes.  Patients will be closely
monitored during and for up to 1 hour following their first VAL401 administration (Cycle 1, Day 1).
5.3.5
Pharmacokinetic assessments
Blood samples will be drawn for the determination of VAL401 concentration-time profiles in serum.


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
Cycle 1, Day 1: pre-dose (0h) then 10, 15, 30 min, 1, 2, 4, 8, 10 and 24 h post-administration.

Cycle 1, Day 15: pre-dose (0h) then 10, 15, 30 min, 1, 2, 4, 8, 10 and 24 h post-
administration.
Note that the ability to take the latter PK samples in a PK profile dosing day will be dependent on the
local site operational procedures.
Nominal PK blood sampling times should be adhered to as closely as possible.  It is essential that the
actual time and date of collection of each blood sample be recorded in the patient’s records and in the
CRF.
The volume of blood to be collected per sample should be 5 mL.
This measurement will be performed by a central laboratory.   Full instructions for blood sample
preparation, aliquoting of samples, sample storage and shipping details will be provided.
5.3.6
Tumour assessment
Tumour assessment during the main part of the study (Cycles 1-6) will follow the RECIST1.1
guidelines.
Assessment will include, as appropriate, the assessment of measurable and any selected non-
measurable lesions by CT scan of chest, abdomen and pelvis at Screening and on the completion of
every 3 cycles. Other assessments e.g. whole body MRI may be assessed as requested by
Investigator.
Additional scans may be performed to confirm a Complete Response or Partial Response or disease
progression.  Other assessments e.g. whole body MRI may be assessed as requested by Investigator.
Patients on study after 6 cycles will have tumour assessment every 3 – 6 cycles depending standard
local clinical practice.
Note that magnetic resonance imaging (MRI) may be used in the event CT is not available, but for
each patient, the radiographic measurement used at Screening/Baseline (i.e., CT or MRI) must be
used serially throughout the duration of study participation.
Early stage antitumour response evaluations should also take into account the guidelines for the
evaluation of immune therapy activity in solid tumors which describes an immune-related response
criteria (Wolchok, et al. 2009).
5.3.7
Biomarker testing
Patients will be asked to provide consent for access to archived tumour tissue (FFPE sections) for
potential future analysis of biomarkers including possible evaluation tumour cell DNA.   Where a
rationale for a specific biomarker assessment has been identified, this consent will allow archived
tumour biopsy material to be tested for this purpose.   A 10 mL blood sample will also be taken at
Screening for collection of germ-line DNA.


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6
STUDY MEDICATION AND ADMINISTRATION
6.1
Study Medication
The Quality Control Standards and requirements for VAL401 study medication are described in
separate release protocols/Certificate of Analysis.
ValiSeek will supply VAL401 as capsules containing either 5 mg or 1 mg VAL401 in lipid excipients.
Composition of VAL401 capsules:
Active Component
Risperidone, 5 mg or 1 mg
Excipients
Rumenic Acid, Capryol PGMC, Capryol 90, Lauroglycol 90
Stability
Stability testing is ongoing.  Please refer to the IMP label for the
Expiry Date associated with the current shelf-life of the product.
Storage and Handling
VAL401 capsules should be stored as supplied in the screw top bottles
in refrigerated storage (2 – 8 oC).
Excipients of human or
animal origin
Hard Gelatin capsule shells
6.2
Selection of Doses in the Study and Duration of Treatment
The starting dose level of VAL401 is 2 mg as a single daily dose on Cycle 1 Day 1, with escalation of
2 mg per day to a maximum of 10 mg per day such that Cycle 1 Day 2 provides 4 mg VAL401 as a
single daily dose, Day 3: 6 mg, Day 4: 8 mg, Day 5 and all subsequent days 10 mg as a single daily
dose.
A treatment cycle is considered as 28 days from (and including) the first day of dosing.   Those
patients who show an improvement or stable disease during treatment in the absence of DLT may
receive up to 6 continuous cycles of therapy which is considered to be a complete treatment course for
the purposes of this clinical trial.  Patients may be permitted to receive more than 6 cycles of VAL401
where their cancer has not progressed on study and their investigator recommends this course of
action.
6.3
Packaging and Labelling
Clinical trial supplies will be provided as screw top bottles containing VAL401 capsules.  Separate
bottles will be supplied containing either 18 x 5 mg VAL401 capsules or 18 x 1 mg VAL401
capsules.
All vials and secondary packaging will be labelled for the purpose of the clinical trial in accordance
with applicable regulatory requirements.
6.4
VAL401 Administration
The maximum dose for any single dose of VAL401 will not exceed 10 mg (2 x 5 mg capsules).
The majority of VAL401 dose administrations (after the dose escalation schedule) will be achieved in
the patient’s home, and not during site visits.  The patient should be encouraged to consider an
appropriate time of day to take the dose, in particular if a patient experiences mild sedation
immediately after dosing, the Investigator should recommend evening dosing in order that the
sedation is resolved before morning waking.


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VAL401 oral capsules should be taken on an empty stomach – either a minimum of 30 minutes before
food or a minimum of 1 hour after food.
VAL401 capsules must be swallowed whole, patients should be directed not to break open the
capsule.
6.5
Storage
The capsules should remain in the screw-top bottles as supplied and stored in refrigerated storage (2 –
8 oC).  The Investigator should ensure the patient has sufficient supplies of capsules to complete the
administration required prior to the next patient visit.
6.6
Replacement of Medication
Sufficient doses of medication will be supplied.   In case the supplies are broken or unusable, they
should be replaced.   Although the Sponsor need not be notified immediately in these cases,
documentation  of  the  use  and/or  loss  of  any  vial  must  be  recorded  by the  pharmacist  on  the
medication accountability form.
6.7
Accountability
The Investigator is obliged to keep sufficient documentation of the delivery, use and destruction or
return of unused, used or partially used IMP.   The documentation must include dates, quantities,
patient numbers, batch numbers or other identification number.  The Investigator may assign some or
all of the Investigator’s duties for drug accountability to an appropriate pharmacist.   Roles and
responsibilities of site staff will be recorded in the Trial Master File.
The Investigator should maintain records that document adequately that the patients were
administered the doses specified in the protocol and reconcile all VAL401 IMP received for the trial.
The local study monitor will be responsible for checking the drug accountability records maintained
by the site during the monitoring visits.
The  medication  provided  for  this  study is  for  use  only  as  directed  in  the protocol.    It is  the
Investigator/Institution’s responsibility to establish a system for handling study drug so as to ensure
that:

deliveries of VAL401 are correctly received by a responsible person;

such deliveries are recorded;

study treatments are handled and stored safely and properly as stated on the label;

study drug is only dispensed to study patients in accordance with the protocol; and

any unused study drug is destroyed locally or returned for destruction in liaison with the study
monitor.
Throughout the study, it must be possible to reconcile delivery records with records of usage and any
destroyed/returned stock.  Records of usage should include the identification of the patient to whom
the study treatment was dispensed and the quantity and date of dispensing.  This record is in addition
to any drug accountability information recorded on the CRF.  Any discrepancies must be accounted
for on the appropriate forms.
The return or destruction of unused drug will be conducted after written approval by the Sponsor, with
appropriate documentation and drug accountability procedures completed following destruction.


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6.8
Treatment Allocation
In order to ensure that the appropriate numbers of patients are enrolled; on identifying a potential
study patient, the Investigator is required to complete a patient registration request form confirming
patient eligibility and requesting a place on the study.  Where appropriate, sites will then receive a
confirmation of enrolment form confirming the enrolment of the patient.  Patients must not be
enrolled until this confirmation is received.  There will be regular communication with study sites
during the trial to ensure Investigators are aware of enrolment status on the trial and suitable times for
patient enrolment.
6.9
Blinding and Procedures for Un-Blinding the Study
This is an open-label study and there are no blinding or un-blinding procedures.
6.10
Permitted and Restricted Concomitant Medications/Treatments
All prescription, non-prescription, or over-the-counter medications (including herbal remedies) given
to, or taken by the patient at study entry (including Screening) and during the study must be clearly
documented on the 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.  In the case of anemia, transfusions with pRBC can be administered.
Prohibited treatments are summarized below:

No other antineoplastic agents will be permitted to be initiated during this study (patients on
stable, long term treatment of any form are permitted providing the medication is not
contraindicated by the SmPC for Risperidone).

No concurrent radiation treatment will be permitted during this study (except for palliative
care e.g. for bone metastases).

Herbal remedies unless pre-approved by the treating physician.


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7
ADVERSE EVENTS AND REPORTING REQUIREMENTS
7.1
Assessment of Safety
All patients who receive treatment with VAL401 will be considered evaluable for safety.  All AEs
will be collected from the time the patient gives informed consent up to and including the 30 day
follow up (Final Study Visit). There will be a baseline medical condition review taken at screening.
AEs, other than the primary disease under evaluation, that worsen in severity or frequency from this
baseline assessment during the study, should be recorded and reported as AEs.  If the Investigator
detects a serious adverse event in a study patient after the end of the period of observation and
considers the event possibly related to prior study treatment or procedures, he or she should contact
the sponsor to determine how the AE should be documented and reported.
7.2
Adverse Event Definition
An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical
condition in a patient or clinical investigation subject administered a medicinal product and which
does not necessarily have a causal relationship with this treatment.   An AE can therefore be any
unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for
example), symptom, or disease temporally associated with the use of a medicinal (investigational)
product, whether or not considered related to the IMP.
During clinical trials, AEs can be spontaneously reported or elicited during open-ended questioning,
examination, or evaluation of a patient.  To prevent reporting bias, patients should not be questioned
regarding the specific occurrence of one or more AEs.
Adverse events  include:  (a) worsening (change  in  nature,  severity,  or  frequency) of conditions
present at the start of the study, (b) concurrent illness, (c) drug interactions, (d) experiences related or
possibly related to concomitant medications, (e) clinically significant abnormal laboratory values or
shifts from baseline, and (f) clinically significant abnormalities in physical examination, vital signs,
weight, or electrocardiogram.
Progression of the disease under study will not be captured as an AE.
Surgical procedures or other therapeutic interventions themselves are not AEs, but the condition for
which the surgery/intervention is required is an AE and should be documented accordingly.
Planned surgical measures and the condition(s) leading to these measures are not AEs, if the
condition(s) was (were) known before the period of observation and did not worsen during study. In
the latter case the condition should be reported as medical history.
7.3
Importance of Adverse Event Reporting
Timely and complete reporting of safety information assists ValiSeek and the Investigators in
identifying any untoward medical occurrence, thereby allowing: (1) safety of study patients; (2) a
greater understanding of the overall safety profile of the investigational drug; (3) recognition of dose-
related investigational drug toxicity; (4) appropriate modification of study protocols; (5)
improvements in study design or procedures; and (6) adherence to regulatory requirements.
7.4
Evaluating Adverse Events
Following the patient’s written consent to participate in the study, all AEs should be collected.
Following the baseline medical history assessment of the patient taken at screening, all identified AEs
must be recorded and described on the appropriate AE page of the CRF.   If known, the diagnosis  of
the  underlying  illness  or  disorder  should  be  recorded,  rather  than  its  individual symptoms.  The


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following information should be captured for all AEs: date of onset and resolution, severity of the
event (see definitions in Section 7.4.1), assessment whether the event was serious or non-serious (see
definitions in Section 7.4.2), Investigator's opinion of the relationship to investigational drug (see
definitions in Section 7.4.6), treatment required for the AE, action taken with IMP, and information
regarding resolution/outcome.
7.4.1
Severity
All AEs (including SAEs) are to be accurately recorded on the AE page of the patient’s CRF.  Each
event will be graded for severity using the classifications of CTCAE v4.03.  For events not addressed
in the CTCAE v4.03, classifications the following grading will apply:

Mild (Grade 1) – Mild; asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated.

Moderate  (Grade  2) – Moderate;  minimal, local  or  noninvasive  intervention indicated;
limiting age-appropriate instrumental Activity of Daily Living (ADL).

Severe  (Grade  3) – Severe  or  medically significant  but  not  immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting
self-care ADL.

Life-threatening (Grade 4) –Life-threatening consequences; urgent intervention indicated.

Death (Grade 5) – related to AE.
7.4.2
Seriousness
A serious adverse event is any untoward medical occurrence that at any dose (including overdose):

Results in death.

Is life-threatening:
o
“Life-threatening” means that the subject was at immediate risk of death at the time
of the serious adverse event; it does not refer to a serious adverse event that
hypothetically might have caused death if it were more severe.

Requires hospitalization or prolongation of existing hospitalization:
o
This means that hospital in-patient admission, or prolongation of hospital stay, were
required for the treatment of the AE, or that they occurred as a consequence of the
event.
o
Visits  to  a  hospital  by  ambulance  or  to  the  emergency  room  without admission
will not be regarded as hospitalization unless the event fulfills any other of the serious
criteria.

Results in persistent or significant disability or incapacity:
o
“Persistent  or significant  disability or incapacity”  means  a permanent  or
significant and substantial disruption of a person’s ability to carry out normal life
functions.

Is a congenital anomaly or birth defect.

Is an important medical event:


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o
Medical and scientific judgment should be exercised in deciding whether expedited
reporting is appropriate in situations where none of the outcomes listed   above
occurred.      Important   medical   events that   may   not   be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may
require intervention to prevent one of the other outcomes listed in the definition
above should also usually be considered serious.   Examples of such events include
allergic bronchospasm requiring intensive treatment in an emergency room or at
home, blood dyscrasias, or convulsions that do not result in inpatient hospitalization,
or the development of drug dependency or drug abuse.
7.4.3
Pregnancy
In principle, pregnancy and the lactation period, or planning to father a child, are exclusion criteria for
clinical studies involving investigational drugs.  In the event of a pregnancy occurring during the
course of this study, ValiSeek must be notified immediately.   If the pregnancy involves a patient
enrolled to the trial, the patient should be immediately withdrawn from study.  The pregnant patient or
the patient’s partner should followed-up during the entire course of the pregnancy and postpartum
period.
Parental and neonatal outcomes must be recorded even if they are completely normal and without
AEs.   Off-spring should be followed up for at least 8 weeks after delivery.   Longer observation
periods may be determined by the sponsor if an adverse outcome of the pregnancy was observed.
Pregnancies occurring during the study up to 90 days after the completion of the study drug must also
be reported to ValiSeek Limited within one working day of becoming aware of them using a clinical
trial pregnancy reporting form. When a “pregnancy is detected without an adverse outcome”, the
Investigator should only complete the SAE form and send this to the sponsor. It should be clearly
stated that no AE was observed.  In this case, there is no need to complete the “adverse event” page in
the case report form.
7.4.4
Misuse and Overdose
Drug misuse and drug overdose should be reported in the same format and within the same timelines
as a serious adverse event, even if they may not result in an adverse outcome.
Overdose  is  defined  as  any dose  administration  where  >10%  over  the  correct  dose  amount  is
administered whether or not associated with an AE.
For monitoring purposes, any case of overdose must be reported on an SAE form as per Section 7.6.
When an “overdose” or “drug misuse” of the investigational product occurs without an AE the
Investigator should complete the SAE form as per section 7.6.  It should be clearly stated that no AE
was observed.  In this case, there is no need to complete the “adverse event” page in the case report
form
If the pharmacy discovers that an overdose has or may have been administered they should contact the
Investigator and study coordinator.


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7.4.5
Investigational Product Complaints
Pharmaceutical technical complaints associated with the investigational product must be reported to
the sponsor immediately.  The same reporting timelines as for serious adverse events apply.
7.4.6
Relationship
All AEs (including SAEs) will be assessed for the relationship of the AE to the study drug using the
following definitions:

Not/Unlikely Related
The AE is not related if exposure to the investigational product has not occurred, OR the occurrence
of the AE is not reasonably related in time, OR the AE is considered unlikely to be related to use of
the investigational product because there are no facts (evidence) or arguments to suggest a causal
relationship AND there is a possible alternative explanation.

Possibly Related
The administration of the investigational product and AE are considered reasonably related in time
AND there are facts (evidence) or arguments to suggest a causal relationship.  This does not exclude
that the AE could be explained by causes other than exposure to the investigational product.*

Probably Related
Exposure to the investigational product and AE are reasonably related in time AND the
investigational product is more likely than other causes to be responsible for the AE, OR is the most
likely cause of the AE.

Definitely Related
There is a reasonable temporal sequence between exposure to the investigational product and the AE,
OR the event follows a known or expected response pattern to the investigational product; AND is
confirmed by improvement on stopping/ reducing the dosage of the investigational product.   It may
also be confirmed by reappearance upon repeated exposure where this is medically and ethically
acceptable.
*For  consideration  of  DLTs  and  subsequent  dose  escalation  decisions,  the  likely  causality  of clinically
significant AEs as defined in  Section 4.2.1, must be carefully considered.
The relationship of the study treatment to an AE will be determined by the Investigator and
subsequently reviewed by the Medical Monitor.
For reporting and data analysis purposes, AEs reported with a causality assessment of “Definitely”,
“Probably” and “Possibly” are to be considered as “having a reasonable causal relationship” to study
drug.  In case of disagreement between the Investigator and the Sponsor’s Medical Monitor the more
conservative assessment will determine the reportability of the case.
7.5
Evaluating Dose Limiting Toxicities (DLTs)/Serious Adverse Events (SAEs)


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DLTs, SAEs classified as DLTs and SAEs will be noted on the AE CRF and on a SAE form.  This
form will classify the event as a DLT only; SAE only; or DLT and SAE.
7.5.1
Unexpected adverse events
The Sponsor will assess all serious adverse events whether they are expected or unexpected.   An
unexpected adverse event is any adverse drug event, the outcome, specificity or severity of which is
not consistent with those noted in the current IB or the SmPC for Risperidone.
7.6
Reporting DLTs/SAEs
Adverse events classified as DLTs and/or SAEs using the definitions above must be recorded on the
SAE form.
The Principal Investigator (or designee) will complete the SAE form and e-mail (or fax if e-mail is not
possible) this and any available supporting documentation of a Serious Adverse Reaction or Adverse
Event to Clinical Accelerator, UK (CRO) and to ValiSeek Limited, UK (Sponsor) and the sponsor
will notify the competent authorities.
The PI must announce AMDM about serious adverse events / serious unexpected adverse reactions in
accordance with Annex 1 (pag. 129 pct. 13.4) MoH Order no. 10 of 14.01. 2002 and MoH Order no.
22 of 12.01.2006.
7.6.1
Reporting SAEs to the IRB or Ethics Committee and Regulatory Authorities
The Investigator must comply with the applicable local regulatory requirements related to the
reporting of SAEs to the required Independent Ethics Committees (IEC).   Other SAEs (i.e. expected
or unrelated SAEs) should be reported per the relevant institution’s procedures.
Until such time that an AE is included in the IB, it should be considered unexpected, regardless of
whether the AE has been the subject of a previous Safety Update.  All expectedness assessments will
be made by the Sponsor.
All events qualifying as SUSARs will be reported to the relevant regulatory authorities according to
local practices.
7.6.2
Follow-up information on an SAE
Collection of complete information concerning SAEs is extremely important.   Thus, follow-up
information which becomes available as the SAE evolves, as well as supporting documentation (e.g.
hospital discharge summaries and autopsy reports), should be collected subsequently, if not available
at the time of the initial report, and immediately sent using the same procedure as the initial SAE
report.  The original SAE form must be kept on file at the study site.  The sponsor will also review
SAE reports for missing information and send queries to the site for resolution as appropriate.
Appropriate diagnostic tests should be performed and therapeutic measures, if indicated, should be
instituted.  Appropriate consultation and follow-up evaluations should be carried out by the Principal


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Investigator (or designee).  An SAE is followed until it is considered resolved; returns to baseline; is
chronically ongoing or explained by the Principal Investigator.


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8
DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES
8.1
End of Study and Study Completion
End of study is defined as the last patient visit or study assessment.  Study completion occurs upon
final database lock and production of the main study report.  Exceptions may be made in the case
where a single patient, or limited number of patients, continue to receive VAL401 after 6 cycles of
treatment.  In such cases End of Study and Study Completion may be defined at a point when all
patients have had the opportunity to complete 6 cycles of IMP.  Additional data from the patient(s)
continuing on treatment will be presented as an Addendum to the CSR upon cessation of treatment.
8.2
Statistical Considerations
Detailed statistical analysis information will be provided separately in the Statistical Analysis Plan
(SAP).  The SAP will detail all data handling rules, including the management of missing values and
the handling of data for withdrawn patients.  The SAP will also outline protocol violation criteria
along with any specific analysis population definitions.   Any deviations to the planned analyses
specified or populations defined within the SAP will be justified in writing and presented within the
final clinical study report.
The clinical database lock will occur after all data are reconciled (i.e. “cleaned”) for all patients who
participate.  Database lock will occur on two occasions – a preliminary database will be generated
from data collected during screening and up to and including the Cycle 1, Day 15 pharmacokinetic
measurement when all patients have completed this section; the final database lock will occur after all
patients have completed the final visit. A single clinical study report will be generated for this study.
The SAP will be finalized and signed before the database lock.
8.3
Demographic and Other Baseline Characteristics
Demographic characteristics will be listed and summarized.  Other baseline characteristics will only
be listed.
8.4
Statistical Methods for Safety Parameters
All safety and tolerability assessments will be based on the safety analysis set, which is defined as all
patients who have received at least one dose of study medication.
Results will be presented using descriptive statistics.  Data collected at screening and up to and
including the Pharmacokinetic measurements collected on Day 15 Cycle 1 will be analysed during a
preliminary analysis point when all patients have reached this stage.  Final analysis will correlate all
remaining data with the preliminary set after last patient, last visit, all data is reconciled and the
complete database is locked.
Vital signs, resting 12-lead ECGs, haematology, coagulation, clinical chemistry and urinalysis data
will be listed by dose group and time-point.
The number and percent of patients experiencing one or more AEs will be summarized by dose level
group, relationship to study drug, and severity.   AEs will be coded using MedDRA terminology. AEs
that have missing onset dates will be considered to be treatment-emergent, unless the stop date is
known to be prior to the first administration of the study medication.


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SAEs and DLTs will also be presented separately.
8.5
Statistical Methods for Pharmacokinetic Parameters
PK parameters will be estimated for each patient using a fully validated version of a recognized
statistical software package.   The following parameters will be derived, where appropriate, from the
individual serum concentration versus time profiles of VAL401.
Parameter
Definition
Cinf
The observed concentration at the end of the administration.
Cmax
The maximum observed concentration.
tmax
The time at which Cmax was apparent.
AUC0-t
The area under the concentration versus time curve from time zero to
the sampling time at the last quantifiable concentration (Ct) at tlast (the
time of the last quantifiable concentration) calculated by the linear
trapezoidal rule.
λz
The apparent terminal rate constant, estimated using the negative slope
of the least square regression analysis of the log concentration versus
time data for the terminal linear portion of the curve.
t½
The apparent terminal half-life, calculated from Loge 2 / λz
AUC0-∞
The area under the concentration-time curve estimated from time zero
to infinity as the sum of the two areas: AUC0-t and AUCextrap, where
AUCextrap is calculated as Ct / λz.
CL
The systemic clearance calculated as: Dose/ AUC0-∞.
Vss
The apparent volume of distribution at steady state calculated as:
Dose/AUC x (AUMC/ AUC0-∞).
Additional PK parameters may be calculated as appropriate.
8.6
Evaluation of Tumour Response (all patients)
Tumour assessment during the main study (Cycles 1-6) will follow RECIST 1.1 (Eisenhauer, et al.
2009) and will include CT scans (or comparable appropriate scan).   Tumour assessment beyond
Cycle 6 will follow local practice.
Response rate will be summarised and a 95% CI calculated.
8.7
Estimated Sample Size
It  is anticipated  that  up  to  20 patients  locally advanced  or metastatic non-small cell lung cancer
cancer may be enrolled in this study.


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9
QUALITY ASSURANCE
9.1
Data Recording
All CRF data will be collected using a paper CRF system. All data will be entered into the CRF by
the Site Staff. These data will then be source data verified and reviewed by the study monitor.  All
queries will be raised and resolved between the monitor and site.
After all queries have been resolved and any summary/analysis populations approved, the database
will be locked and the data released for summary and analysis.
9.2
Study Monitoring
The assigned study monitor will review the progress of the study on a regular basis to ensure adequate
and accurate data collections.  Monitoring site visits to review CRFs, patient case notes,
administrative documentation including the Investigator Site File and frequent telephone/e-mail
communications with site will be performed throughout the study.
At each study monitoring visit the Investigator will make available all records pertaining to the study.
To allow sufficient time to assemble documentation for the study monitor, monitoring visits will be
confirmed in advance of planned visits.
9.3
Clinical Study Audit
The Sponsor, Sponsor representative or external regulatory agency may at any time during or after
completion of the study conduct a GCP audit.  Prior notice will be given to each site selected for audit
in advance of a planned audit.
9.4
Clinical Study Report
The results of the study will be presented in an integrated clinical study report according to ICH
guidelines.
9.5
Data Retention and Availability
The Investigator is required to maintain copies of all essential study documentation, including the Site
Study File, all CRF data (including the full audit trail and all data queries), signed informed consent
forms, and records for the receipt and disposition of study medications, for a period of at least five
years after study completion, as specified by ICH GCP and longer if required by local or regulatory
authorities.
During the study, the Investigator must make study data accessible to the study monitors, the Sponsor
(or a third party auditor assigned by the Sponsor), and relevant IRB/IECs and regulatory agencies.  A
file for each patient must be maintained that includes the signed informed consent form and all source
documentation related to that patient.  The Investigator must ensure the availability of source
documents from which the information in the CRF was derived.


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10
ETHICS REVIEW/INFORMED CONSENT
The final study protocol and patient informed consent form will be approved by the appropriate
independent ethics committee for each investigational site.  Approval will be received in writing
before initiation of the study.
Changes to the protocol during the trial will be documented as amendments.   Depending on the
contents of the amendment and local legal requirements, the amendment will be submitted for
approval to the relevant ethics committees and to the relevant competent authorities prior to
implementation. Exceptions are cases of changes made to protect patient safety, which will be
implemented immediately.
If an amendment substantially alters the trial design, increases the potential risk to the patients, affects
the treatment of the patient or might otherwise influence the willingness of the patient to participate in
the trial, then the information sheet must be revised and submitted to the relevant ethics committees
and, where necessary, to the relevant competent authorities, for review and approval.  When a patient
is currently undergoing trial procedures and is affected by the amendment, then the patient must be
asked to consent again using the new information sheet.
10.1
Ethical Conduct of the Study
The study will be conducted in accordance with ICH GCP, the Declaration of Helsinki and the
requirements of local regulatory authorities and ethics committees.
10.2           Informed Consent
The principles of informed consent in the Declaration of Helsinki and GCP Guidelines will be
implemented before any protocol-specific procedures or interventions are carried out.
All patients will be informed that participation is voluntary and that they can cease participation at
any time without necessarily giving a reason and without any penalty or loss of benefits to which they
are entitled.
With the help of the information sheet the patient will be informed about the IMP and anticipated
effects, and the reason, design and implication of the trial.    The patient must give consent to
participate prior to enrolment in the trial.  This consent must be given in writing.  The Investigator
who conducts the informed consent discussion must also sign.  The Investigator may delegate this
responsibility to a suitably qualified member of the study team e.g. sub-investigator, if permitted by
local regulations.  This delegation of responsibility must be recorded in the study file.   By giving
signed consent, the patient will confirm that their participation is voluntary and that they will follow
the instructions of the Investigator and answer the questions asked.  Signatures must be personally
dated.
The signed and dated consent form will be kept by the Investigator.  Prior to participation in the trial,
the patient should receive a copy of the signed and dated written informed consent form.
The consent form and information sheet must include all elements required by law, local regulations,
GCP and ICH guidelines including consent to allow the Sponsor, Sponsor representative or external


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regulatory auditor to review the patient’s medical records.  This gives permission to examine, analyze,
verify and reproduce any records and reports that are important to the evaluation of the trial.
Any party with direct access must take all reasonable precautions within the constraints of the
applicable regulatory requirement(s) to maintain the confidentiality of the patient’s identities and
Sponsor’s proprietary information.  It is the study monitor’s responsibility to verify that each patient
has consented, in writing, to direct access.
10.3
Insurance
Insurance for the patients participating in this trial will be arranged by ValiSeek, as Sponsor of the
clinical trial, in accordance with the regulatory requirements of the countries involved.  A copy of the
country-specific insurance certificates will be held in the Trial Master File and in the Investigator site
file.


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11
PUBLICATION POLICY
The original CRFs and all data generated during the clinical study using the given protocol will
become the property of the Sponsor.
Any proposed publication or presentation (including a manuscript, abstract or poster) for submission
to a journal or scientific meeting should be sent to the Sponsor for review at least one month prior to
submission.  No single centre or groups of centres may publish individually.  Publications arising
from this clinical study will include all Investigators and Sponsor representatives as authors.  The
Sponsor's comments on the proposed publication shall be considered in good faith by the authors. The
Sponsor may delay such submission by a maximum of ninety (90) days if it reasonably believes that
publication of results may compromise its intellectual property rights, or else require that such
information or data are removed from the proposed publication.  Publication of the results will not
include confidential information without the permission of the Sponsor.  Approval of such requests to
submit for publication will not be unreasonably withheld.
The Sponsor may announce quality assured summary data in order to comply with Financial
Regulatory Authorities, whilst ensuring, so far as possible, that such announcements will not
compromise the Investigators ability to publish the data in appropriate scientific forums.
This publication policy will be reviewed to ensure compliance with the anticipated changes in EU and
Georgian legislation in 2016.


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REFERENCES
Corner J, Hopkinson J, Fitzsimmons D, Barclay S and Muers M. (2005). Is late diagnosis of
lung cancer inevitable? Interview study of patients' recollections of symptoms before
diagnosis. Thorax 60:314-319.
Carlson E, Marquez R, Du F, Wang, Y, Xu L, Yan S (2015).  Overexpression of 17Beta-
hydroxysteroid dehydrogenase type 10 increase pheocytoma cell growth and resistance to cell
death.  BMC Cancer 15:166
D'Addario G, Fruh M, Reck M, Baumann P, Klepetko W and Felip E. (2010). Metastatic
non-small-cell lung cancer: ESMO Clinical practice guidelines for diagnosis, treatment and
follow-up. Annals of Oncology 21 (5):116-119.
Eisenhauer EA1, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij
J. (2009). New response evaluation criteria in solid tumours: revised RECIST guideline
(version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
Gazdar A.F. (2010). Should we continue to use the term non-small-cell lung cancer? Annals
of Oncology 21 (Supplement 7)
Kissinger C, Rejto P, Pelletier L, Thomson J, Showalter R, Abreo M, Agree C, Margosiak S,
Meng J, Aust R, Vanderpool D, Li B, Tempczyk-Russell A, Villafranca E (2004). Crystal
Structure of Human ABAD/HSD10 with a bound inhibitor: Implications for design of
Alzheimer’s disease therapeutics. J. Mol. Biol: 342, 943-952.
Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr K and Peters S. (2014). Metastatic
non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis,
treatment and follow-up. Annals of Oncology August 11:1-13.
Schiller J, Harrington D, Belani C, Langer C, Sandler A, Krook J, Zhu J and Johnson D.
(2002). Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
The New England Journal of Medicine 346 (2):92-98.
Sculier J.P. (2013). Nonsmall cell lung cancer. European Respiratory Review 22:(127),33-36


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APPENDIX A: ECOG PERFORMANCE STATUS
Eastern Co-operative Oncology Group (ECOG) Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary
nature, e.g. light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than
50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP Toxicity and
response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982; 5: 649-655.


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APPENDIX B: NCI CTCAE v4.03
A complete copy of the NCI CTCAE v4.03 will be held in each Site Study File.
Please use link below to access most current version of the NCI CTCAE.
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 .


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APPENDIX C: LOCAL LABORATORY PARAMETERS
Clinical chemistry
Haematology, including
coagulation screen
Urinalysis
Calcium
Red cell count
Glucose
Total protein
Hemoglobin
Protein
Albumin
Hematocrit
Bilirubin
Total bilirubin
Absolute reticulocyte count
Ketones
Alanine transaminase (ALT, SGPT)
Platelet count
Blood
Aspartate transaminase (AST, SGOT)
White blood cells
pH
Alkaline phosphatase
Leucocyte differential count (% &
absolute)
Pregnancy test as required
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