Clinical Trials Register

Summary
EudraCT Number:	2017-000144-18
Sponsor's Protocol Code Number:	CDKO-125a-010
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-30
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Greece - EOF

A.2

EudraCT number

2017-000144-18

A.3

Full title of the trial

Phase IIA Exploratory Study of Oral Milciclib Maleate in Patients with Unresectable or Metastatic Hepatocellular Carcinoma

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study of milciclib in patients with liver cancer

A.3.2

Name or abbreviated title of the trial where available

Ph IIA Study of Milciclib in Patients with Unresectable/Metastatic HCC

A.4.1

Sponsor's protocol code number

CDKO-125a-010

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Tiziana Life Sciences Plc
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Tiziana Pharma Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CLIOSS S.r.l.
B.5.2	Functional name of contact point	Project Management
B.5.3	Address:
B.5.3.1	Street Address	Viale Pasteur 10
B.5.3.2	Town/ city	Nerviano (MI)
B.5.3.3	Post code	20014
B.5.3.4	Country	Italy
B.5.4	Telephone number	+393480840579
B.5.5	Fax number	+390331581659
B.5.6	E-mail	monica.miani@clioss.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Milciclib maleate
D.3.2	Product code	PHA-848125AC
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Milciclib maleate
D.3.9.1	CAS number	802539-81-7
D.3.9.2	Current sponsor code	PHA-848125AC
D.3.9.3	Other descriptive name	MILCICLIB MALEATE
D.3.9.4	EV Substance Code	SUB180509
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Milciclib maleate
D.3.2	Product code	PHA-848125AC
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Milciclib maleate
D.3.9.1	CAS number	802539-81-7
D.3.9.2	Current sponsor code	PHA-848125AC
D.3.9.3	Other descriptive name	MILCICLIB MALEATE
D.3.9.4	EV Substance Code	SUB180509
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Milciclib maleate
D.3.2	Product code	PHA-848125AC
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Milciclib maleate
D.3.9.1	CAS number	802539-81-7
D.3.9.2	Current sponsor code	PHA-848125AC
D.3.9.3	Other descriptive name	MILCICLIB MALEATE
D.3.9.4	EV Substance Code	SUB180509
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Uunresectable or metastatic hepatocellular carcinoma

E.1.1.1

Medical condition in easily understood language

Liver tumor

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	PT
E.1.2	Classification code	10073071
E.1.2	Term	Hepatocellular carcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety profile and tolerability of repeated administrations of milciclib in Child-Pugh "A" unresectable HCC patients who failed or are not eligible for Sorafenib or who actively refused it (presenting as naïve, progressing, recurrent or metastatic disease).

E.2.2

Secondary objectives of the trial

• To document any antitumor activity of milciclib in patients with recurrent or metastatic unresectable HCC who have failed the standard therapy or who are not able to tolerate the standard therapy or who actively refused it.
• To assess additional markers of tumor control to further characterize the efficacy profile of milciclib.
• To evaluate the pharmacokinetic profile of milciclib and its metabolite in Child Pugh "A" HCC patients.
Exploratory Objective: To evaluate the role of predictive and/or pharmacodynamic biomarkers of response to milciclib.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients with diagnosis of HCC, confirmed by histology or radiology according to AASLD/EASL criteria prior to the start of the investigational product. Imaging characteristics should be retrieved from at least a 3-phase liver protocol CT or MRI with target tumor lesion(s) demonstrating arterial hyper-enhancement and wash-out in the venous phase;

- Tumor stages eligible for the study are defined as:
a. HCC within the Barcelona Clinic Liver Cancer (BCLC) stage C. In case of portal vein thrombosis (PVT) an associated target lesion in the liver parenchyma should be clearly defined. PVT without associated target lesion are not eligible to the study;
b. Untreatable post-chemoembolization (TACE) or post-radioembolization (TARE) progression defined as BCLC stage B or C with radiographic progression according to mRECIST after TACE or TARE not eligible for further surgical or loco-regional therapy;
c. Recurring HCC non eligible for pre-transplant downstaging protocols or for resection;

- Patients must have failed sorafenib treatment or be intolerant to sorafenib or actively refusing sorafenib
a. Failing sorafenib treatment is defined if after ≥ 14 days of therapy (not necessarily consecutive) radiology progression is ascertained according to mRECIST;
b. Intolerant to sorafenib treatment is defined as a sorafenib related Grade 2 or greater adverse event (CTC-AE) that continues or recurs after sorafenib treatment interruption for 7 days or dose reduction;
c. Active refusal should be documented by a written and signed patient declaration to be filed in the clinical records;

- Child-Pugh score 6 (class A);

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;

- Local or loco-regional therapy (i.e., surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radioembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed ≥4 weeks prior to study entry with documentation of progressive or recurrent disease;

E.4

Principal exclusion criteria

- Prior use of any systemic anti-cancer therapy (including experimental agents and immunotherapy) except for sorafenib and second line tretatment with regorafenib discontinued for intolerance within 14 days;

- Known fibrolamellar HCC or mixed hepato-cholangiocarcinoma;

- Grade 3 oesophageal varices, regardless of previous bleeding episodes on endoscopy perfomed no more than in the last 12 months;

- Clinical meaningful ascites defined as CTCAE Grade≥2. Patient who have been on a stable medication regimen for at least 2 months to manage ascites are eligible if they show no ascites at the clinical examination. Patients with clinically undetectable ascites who are Child A with detectable ascites at CT/MRI are eligible to the protocol;

E.5 End points

E.5.1

Primary end point(s)

Overall safety profile, evaluated on the basis of laboratory (i.e. hematology and blood chemistry, urinalysis, vital signs, ophthalmologic examinations) and adverse events emerging during the trial will be determined. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 will be used for the severity grading of vital signs, adverse events and of hematological and blood chemistry abnormalities.

E.5.1.1

Timepoint(s) of evaluation of this end point

From the signature of Informed Consent to 30 days after last dose intake.

E.5.2

Secondary end point(s)

1. Objective Response Rate (ORR), i.e., confirmed CR + confirmed PR. The objective tumor assessment will be made according to the modified Response Evaluation Criteria In Solid Tumors (mRECIST) criteria for HCC. Conventional RECIST 1.1 will be also assessed. ORR will be assessed locally and confirmed by an Independent Central Review.
2. Progression-free survival (PFS) evaluated since study treatment start to progression, based on mRECIST tumor assessment, or death for any causes.
3. Time to progression (TTP) evaluated since study treatment start to progression, based on mRECIST tumor assessment or death due to disease progression in the absence of previous documented PD.
4. Proportion of evaluable patients known to be alive and progression free based on mRECIST tumor assessment at ≥3 months since study treatment start out of the total number of evaluable patients (TTP-3 months).
5. Duration of overall response (DoR), measured from the time measurement criteria are first met for CR/PR, based on mRECIST tumor assessment, until the first date that recurrence or PD is objectively documented or death date due to tumor progression in the absence of previous documented PD.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. At screening, during treatment at Day 45, at Day 90 and in the follow-up period at Day 180 for patients not progressed at previous assessment;
2, 3, 5) All study period;
4) After 3 months since treatment started;

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Greece

Israel

Italy

Turkey

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visit last subject including follow up

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Standard medical care for the condition

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-05-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-06-20

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