Clinical Trials Register

Summary
EudraCT Number:	2020-000954-86
Sponsor's Protocol Code Number:	107CS-5
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-08-04
Trial 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

Bulgarian Drug Agency

A.2

EudraCT number

2020-000954-86

A.3

Full title of the trial

A Multinational, Multicenter, Open-label, Phase II/III Clinical Trial to Evaluate the Efficacy and Safety of Oral Paclitaxel (DHP107) Compared to IV Paclitaxel as First-line Therapy in Patients with Recurrent or metastatic HER2 negative Breast Cancer

''Международно, многоцентрово, отворено, фаза 2/3, клинично
изпитване за оценка на ефикасността и безопасността на паклитаксел
за перорално приложение (DHP107) в сравнение с паклитаксел за
интравенозно приложение като първа линия на терапия при пациенти с
рецидивиращ или метастатичен HER2-отрицателен рак на гърдата''

A.3.1

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

A.4.1

Sponsor's protocol code number

107CS-5

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	Daehwa Pharmaceutical Co., Ltd.
B.1.3.4	Country	Korea, Republic of
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	Daehwa pharmaceutical Co., Ltd.
B.4.2	Country	Korea, Republic of
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	HT Research BG Ltd.
B.5.2	Functional name of contact point	Nenad Nikolic
B.5.3	Address:
B.5.3.1	Street Address	30-32 Gen. E.I.Totleben blvd., fl. 2, Krasno Selo District
B.5.3.2	Town/ city	Sofia
B.5.3.3	Post code	1606
B.5.3.4	Country	Bulgaria
B.5.4	Telephone number	+359886699621
B.5.5	Fax number	+35929051905
B.5.6	E-mail	nenikolic@Hungarotrial.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	Yes
D.2.1.1.1	Trade name	Liporaxel
D.2.1.1.2	Name of the Marketing Authorisation holder	Daehwa Pharmaceutical Co., Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	Korea, Republic of
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	Liporaxel
D.3.2	Product code	DHP107
D.3.4	Pharmaceutical form	Oral solution
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	Paclitaxel
D.3.9.1	CAS number	33069-62-4
D.3.9.2	Current sponsor code	DHP107
D.3.9.4	EV Substance Code	SUB09583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	Comparator
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	Yes
D.2.1.1.1	Trade name	Taxol
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Co.
D.2.1.2	Country which granted the Marketing Authorisation	Taiwan
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	Taxol
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Paclitaxel
D.3.9.1	CAS number	33069-62-4
D.3.9.3	Other descriptive name	intravenous paclitaxel
D.3.9.4	EV Substance Code	SUB09583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
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

Recurrent or metastatic HER2 negative Breast Cancer

E.1.1.1

Medical condition in easily understood language

Breast cancer patients with recurrent or metastatic HER2 gene negative

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10006198
E.1.2	Term	Breast cancer recurrent
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate the efficacy of oral paclitaxel by comparing the progression-free survival (PFS) of treatment with oral paclitaxel and IV paclitaxel in subjects with Recurrent or metastatic HER2 negative breast cancer.

E.2.2

Secondary objectives of the trial

To assess oral paclitaxel compared to IV paclitaxel in terms of the following endpoints in subjects with recurrent or metastatic HER2 negative breast cancer:
- Objective response rate (ORR)
- Overall survival (OS)
- Time to treatment failure (TTF)
- Disease control rate (DCR)
- Quality of life (QoL) as the EQ-5D-3L
- Safety

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Subjects who are ≥ 19 years of age on the date of written informed consent.
2) Subjects with confirmation of primary, recurrent or metastatic HER2 negative breast cancer based on histopathology examination (tumor characteristics should be confirmed by histological or cytological evaluation). However, in case of a metastasis or recurrence, it is not required to be verified again by histopathology, i.e it is possible to register with imaging alone.
(1) Subjects are eligible for the study regardless of hormone receptor status (ER/PR positive or negative).
(2) ER/PR(+) is defined as cells expressing hormone receptors >1% in immunohistochemistry (IHC) analysis of collected samples.
3) HER2-negative from tumor sample (primary or metastatic) is confirmed with one of the followings as NCCN guiline 20197 (HER2 test should be performed using samples of metastatic site, if metastasis is confirmed and samples can be collected from the metastatic lesions.)
(1) HER2 negative by validated immunohistochemistry (IHC) assay:
- IHC 0, 1+
- When IHC 2+, must reflex test with ISH (if same specimen), or order new test with IHC or dual probe in situ hybridization (ISH) (if new specimen available)
(2) HER2 negative by validated dual-probe ISH assay:
- HER2/CEP17 ratio < 2.0 and average HER2 copy number < 4.0 signals/cell
(3) HER2 negative by concurrent IHC and ISH results:
- HER2/CEP17 ratio ≥ 2.0 and average HER2 copy number < 4.0 signals/cell and concurrent IHC 0-1+ or 2+
- HER2/CEP17 ratio < 2.0 and average HER2 copy number ≥ 6.0 signals/cell and concurrent IHC 0-1+
- HER2/CEP17 ratio < 2.0 and average HER2 copy number ≥ 4.0 and <6.0 signals/cell and concurrent IHC 0-1+ or 2+
4) Subjects with life expectancy ≥ 12 weeks
5) Subjects with Eastern Cooperative Oncology Group (ECOG) performance status 0-1
6) Subjects with measurable or evaluable lesions identified by RECIST version 1.1. (However, for phase II study, only subjects with measurable lesions can be enrolled.)
7) Subjects with confirmed adequate hematologic, renal and liver function as follows:
(1) Absolute neutrophil count (ANC) ≥ 1,500/μL
(2) Platelet ≥ 100,000/μL
(3) Hemoglobin ≥ 9.0 g/dL
(4) Serum creatinine ≤ 1.5 X ULN (but, subjects with CrCl or eGFR ≥ 60 mL/min may participate)
(5) Serum calcium level ≤ 12 mg/dL
(6) Total bilirubin ≤ 1.5 X ULN (except for elevated total bilirubin due to Gilbert’s Syndrome)
(7) Liver function tests:
- If there is no evidence of liver metastases: ALT and AST ≤ 2.5 x ULN
- If liver metastases are documented: ALT and AST ≤ 5 x ULN
8) If subjects with central nervous system metastasis who should be stable for more than 4 weeks prior to randomization
(1) If subjects have a history of steroid administration, such patient can participate if he/she have discontinued steroid, or reduce or maintain dexamethasone administration of up to 4mg per day (or equivalent dosage) for more than 4 weeks prior to randomization date.
(2) Brain-imaging should be used to confirm that there are no new lesions and if subjects have symptoms of CNS metastasis, the investigator should use brain-imaging to confirm such case, at the investigator’s discretion.
9) Subjects who understand and are willing to comply with the protocol at the judgment of the investigator
10) Subjects who voluntarily agree to participate in the study and sign the informed consent form

E.4

Principal exclusion criteria

1) Subjects expected to have hypersensitivity to active ingredient and any component of this investigational product.
2) Subjects who previously received drugs of taxane class (subjects who administer the last dose of drug of taxane class ≥ 1 year ago as from the randomization day and have recurrence confirmed can be enrolled)
3) Subjects receiving chemotherapy for recurrent or metastatic HER2 negative breast cancer before screening for the study. However, the following subjects should be allowed to participate:
(1) Subjects who had the last administration of adjuvant or neoadjuvant chemotherapy from randomization for prior breast cancer that is not recurrent or metastatic, and its toxic symptoms have disappeared.
(2) ER/PR(+) subjects can be enrolled regardless of lines of endocrine therapy. (Alone or with CDK4/6 inhibitors, or mTOR inhibitors.)
4) Subjects who received radiotherapy within 2 weeks from the randomization day (subjects who have completed local radiotherapy as palliative therapy for the purpose of pain relief for sites (eg, sites of bone metastasis, etc.) other than the target lesion and have recovered from the resulting acute toxicity (eg, bone marrow suppression) can participate.)
5) Subjects with confirmed heart failure of New York Heart Association (NYHA) class 2 or higher, or clinically significant arrhythmia uncontrolled by drug treatments, at the time of study entry.
6) Subjects with confirmed cardiovascular disease (including unstable angina pectoris, myocardial infarction, stroke, and transient ischemic attack) that occurred within 24 weeks prior to study entry, which is deemed to be clinically significant by the investigator
7) Subjects whose left ventricular ejection fraction (LVEF) measured by echocardiogram, MUGA scan, or standard procedures of study site is < lower limit of normal (50%, if the institutional lower limit of normal is not set) within 12 weeks prior to study entry
8) Subjects with uncontrolled hypertension at the time of randomization (SBP > 140 mmHg or DBP > 90 mmHg despite drug treatments)
9) Subjects who have a history of active hepatitis B or C, or hepatobiliary disorders confirmed by medical records or medical examination
[However, the following subjects may participate:
(1) Subjects with Gilbert’s Syndrome, asymptomatic gallstone, liver metastases, or stable chronic liver disease may participate at the discretion of the investigator.
(2) Healthy carriers of hepatitis B who agree on prophylactic antiviral agent during chemotherapy or C virus can participate if HBV-DNA or HCV RNA titer is negative]
10) Those who have been confirmed to be positive for human immunodeficiency virus (HIV) through medical records or medical examination
11) Confirmed neuropathy grade ≥ 2 (based on CTCAE v4.03) at the time of study entry
12) Subjects with confirmed uncontrolled intercurrent disease or condition including significant mental disease or social status which, in the investigator's judgment, may affect compliance with study procedures
13) Subjects with a history of primary malignancy other than breast cancer. However, the subjects should be allowed to participate if:
(1) It has been at least 5 years and they are disease-free since completion of tumor treatment
14) Subjects who are expected to newly start prophylactic use of bisphosphonate or RANKL inhibitor for bone metastasis during clinical study, at the discretion of investigator. (However, subjects on the drug for bone metastasis or osteoporosis just before the IP administration can participate and are permitted for concomitant administration during the study. But in that case, the same Dose and Usage should be maintained during the clinical trial period).
15) Subjects determined inappropriate to orally administer the IP at the time of study participation based on the investigator's judgment
(1) Clinically significant or uncontrolled congenital or acquired gastrointestinal disease
(2) Subjects with confirmed diseases that may interfere with the IP's administration, transfer to digestive tract, or absorption including ileus and inflammatory bowel disease (Crohn’s disease and ulcerative colitis)
16) Pregnant or breast-feeding women
17) Subjects of childbearing women and men (including partners) who are unwilling to remain abstinent nor use adequate contraception during the study and at least 12 weeks after the end of treatment
18) Subjects who have participated in other clinical trials/studies within 2 weeks prior to the administration of this IP or who are scheduled to participate in other clinical trials/studies during this clinical trial period. (However, if the subject participated in control arm of active drug with market approval, he/she can be allowed by investigator’s discretion. Also, subjects who participated in an observational study with minimal medical intervention (e.g. blood or urine test) can also be allowed by investigator’s discretion.)
19) Unable according to investigator

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival (PFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Progression Free Survival (PFS) will be assessed up to 18 months.

E.5.2

Secondary end point(s)

- Objective response rate (ORR)
- Overall survival (OS)
- Time to treatment failure (TTF)
- Disease control rate (DCR)
- Quality of life (QoL) as the EQ-5D-3L
- Safety

E.5.2.1

Timepoint(s) of evaluation of this end point

- Objective Response Rate (ORR) will be followed every 6 weeks until progression, an expected average of 9 months.
- Overall Survival(OS) will be followed until 6 months after the last participant is enrolled, assessed minimum to 18 months.
- Time to Treatment Failure(TTF) will be followed through study completion, an expected average of 4.5 year.
- Disease Control Rate(DCR)will be followed through study completion, an expected average of 4.5 year.
- Quality of life(QoL) will be assessed C1D1, C2D1, C4D1, C7D1, C10D1 (each cycle is 28 days) and study completion, up to 18 months.
- Safety will be assessed up to 28 days after last investigational product administration.

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

China

Korea, Republic of

Bulgaria

Hungary

Serbia

E.8.7

Trial has a data monitoring committee

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

End of study is performed for all subjects when the last subject reaches their EOT or passes 18 months from the enrollment.

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

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:

556

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

556

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Elderly

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

120

F.4.2.2

In the whole clinical trial

556

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)

All subjects will have safety follow-up visit 28 days (+7 days) from the date of the last dose. In safety follow-up visit, adverse events, concomitant medications, subsequent anti-cancer treatments, and
death will be investigated. The survival follow-up will be performed every 12 weeks (±14 days) for the first year, and every 24 weeks (±14 days) from the second year onwards up to 5 years.

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

2020-10-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-08-17

P. End of Trial
P.	End of Trial Status	Ongoing

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IMP with orphan designation in the indication
Orphan Designation Number:
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