Clinical Trials Register

Summary
EudraCT Number:	2020-000960-52
Sponsor's Protocol Code Number:	107CS-6
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-07-29
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

Czechia - SUKL

A.2

EudraCT number

2020-000960-52

A.3

Full title of the trial

A Multi-national, Multi-center, Open-label, Phase 2 Clinical Trial to Evaluate the Efficacy, Safety and Pharmacokinetics of DHP107 (Liporaxel®, Oral Paclitaxel) Compared to IV Paclitaxel in Patients with Recurrent or Metastatic Breast Cancer

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-6

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	Non-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	Daehwa Pharmaceutical Co., Ltd.
B.5.2	Functional name of contact point	Project leader
B.5.3	Address:
B.5.3.1	Street Address	2145 Nambusunhwan-ro, Seocho-gu
B.5.3.2	Town/ city	Seoul
B.5.3.3	Post code	06699
B.5.3.4	Country	Korea, Republic of
B.5.4	Telephone number	+8226716-1051
B.5.5	Fax number	+822587-0566
B.5.6	E-mail	jhjang@dhpharm.co.kr

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.3.11 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	PACLITAXEL 100MG INJECTION 16.7ML
D.2.1.1.2	Name of the Marketing Authorisation holder	Hospira
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	PACLITAXEL 100MG INJECTION 16.7ML
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.3.11 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 overall response rate (ORR) 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 evaluate the safety and tolerability and establish the pharmacokinetic (PK) profile of DHP107 in patients with Recurrent or metastatic HER2 negative breast cancer.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Subjects who are ≥18 years of age on the date of written informed consent.
2.Subjects with confirmed diagnosis of recurrent or metastatic breast cancer based on histopathology examination (tumor characteristics should be confirmed by histological or cytological evaluation):
1)Subjects are eligible for the study regardless of hormone receptor status (ER/PR-positive or -negative)
2)ER/PR-positivity is defined as >1% cells expressing hormone receptors from the metastatic or primary site based on immunohistochemistry (IHC).
3.Subjects with diagnosis of HER2-negative breast cancer that was confirmed by IHC or in situ hybridization (ISH) assessment of tumor samples (from primary or metastatic site) in any of the following cases (If metastasis is confirmed and it is feasible to obtain the tumor sample from the metastatic site, HER2 status assessment must be performed using the sample from the metastatic site):
1)IHC Assessment
• IHC score of 0 or 1+
• In case of IHC score of 2+, ISH must be performed to confirm HER2-negative breast cancer
2)ISH Assessment
• Dual-probe HER2/CEP17 ratio <2 and average HER2 copy number of <6.0 signals per cell.
• Single-probe testing with an average HER2 copy number between 4-6 should be repeated with dual-probe testing.
4.Subjects who have received up to 3 lines of chemotherapy for advanced disease. Surgery, radiotherapy, and endocrine (hormone) therapy are not counted as line of therapy.
5.Subjects who have a life expectancy of ≥12 weeks.
6.Subjects who are able to take oral medication.
7.Subjects who have a performance status of ≤2 on the Eastern Cooperative Oncology Group (ECOG) scale.
8.Subjects who have measurable disease according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST version 1.1).
9.Subjects who have adequate organ functions as indicated by the following laboratory values:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L;
• Platelet ≥ 100 x 109/L;
• Hemoglobin ≥ 9 g/dL;
• Serum creatinine ≤ 1.5 x institutional ULN (however, a subject who has a CrCl or eGFR ≥ 60 mL/min is eligible);
• Serum total bilirubin ≤1.5 X ULN (however, higher bilirubin levels due to Gilbert’s syndrome are allowed);
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (or ≤ 5 x ULN for patients with liver metastases).
10.Subjects who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and procedures.
11.Subjects who have voluntarily agreed to participate by giving written informed consent.
12.Women of childbearing potential who have negative pregnancy test results at the screening visit and men with female partners of childbearing potential must agree to use highly effective contraception from the time of providing informed consent until 90 days after last dose of study drug. For female subjects, a double-barrier method of contraception, such as contraceptive cap (vaginal diaphragm or cervical caps for contraception), intra uterine devices (IUDs), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion is accepted; for male subjects, a condom with spermicide or total abstinence is accepted. Use of oral contraceptives is not allowed as a method of birth control.

E.4

Principal exclusion criteria

1.Subjects who have history of severe hypersensitive reaction to the active ingredient or any excipients of DHP107 or IV paclitaxel.
2.Subjects who have received prior taxane therapy in the metastatic setting. However, 1) subjects who received taxane therapy >12 months prior to study entry and 2) did not have disease progression while on taxane, can be eligible for the study.
3.Subjects whose adjuvant or neoadjuvant treatment for early stage breast cancer was completed within 6 months prior to entry into the study.
4.Subjects who received radiation therapy within 2 weeks of randomization (however, subjects who completed local radiation therapy as palliative care to alleviate pain from non-target lesions [e.g., sites of bone metastasis] and recovered from relevant acute toxicity [e.g., bone marrow suppression] are eligible for the study).
5.Subjects who were diagnosed with New York Heart Association (NYHA) Class II congestive heart failure or have clinically significant arrhythmia not controlled by medication prior to study entry.
6.Subjects who developed cardiovascular disease (unstable angina, myocardial infarction, stroke, and transient ischemic attack) within 24 weeks prior to study entry, which is deemed to be clinically significant by the Investigator.
7.Subjects with known active hepatitis B or C infection, or hepatobiliary disease, or known history of immunodeficiency virus infection (However, subjects with Gilbert’s Syndrome, asymptomatic gallstones, or stable chronic liver disease are, at the discretion of the investigator, eligible for the study. Subjects who are hepatitis B carriers may be eligible if they are on antiviral therapy 2 weeks prior to study entry).
8.Subjects with neuropathy grade ≥2 based on CTCAE v4.03 at the time of study entry.
9.Subjects with uncontrolled medical or mental illness that, in the Investigator’s judgement, could affect treatment tolerability or compliance.
10.Subjects diagnosed with other malignant primary tumor with the exception of the following:
• Malignancy diagnosed at least 5 years previously without evidence of recurrence or persistent disease.
• The complete excision of basal/squamous cell carcinoma or papillary thyroid carcinoma or the complete treatment of cervical intraepithelial neoplasia or other in situ carcinoma.
11.Subjects with symptomatic, untreated metastases to the central nervous system (CNS) at the time of screening. Subjects with treated CNS metastases that are documented to be stable by CT or MRI imaging 4 weeks after completion of radiation and who do not require systemic corticosteroids are eligible.
12.Subjects who are currently receiving (or unable to stop use the day before the first dose of DHP107 and throughout the study) prescription or non prescription medications or other products known to be moderate or potent inhibitors/inducers of CYP3A4, P-gp, or CYP2C8.
13.Subjects who cannot tolerate oral administration as determined by the Investigator including the following:
• Subjects with innate or acquired serious or uncontrolled gastrointestinal disease
• Subjects with bowel obstruction or inflammatory bowel disease (e.g., Crohn’s disease, chronic inflammation) that could affect the administration and absorption of oral medication
• Subjects with uncontrolled diarrhea (e.g., Grade 4 ≥ diarrhea or Grade 3 ≥ diarrhea which lasts for 7 days or more, even when symptomatic therapy is performed)
14.Pregnant or breastfeeding women
15.Subjects who have received any investigational drugs or devices within 2 weeks or 5 times the half-life of the previous investigational product (whichever is longer) prior to randomization.

E.5 End points

E.5.1

Primary end point(s)

Overall Response Rate (ORR)

E.5.1.1

Timepoint(s) of evaluation of this end point

Objective Response Rate (ORR) will be assessed up to 18 months.

E.5.2

Secondary end point(s)

•Pharmacokinetics
•Progression-free survival (PFS)
•Overall survival (OS)
•Time-to-treatment failure (TTF)
•Duration of response
•Disease control rate (DCR)
•Quality-of-life questionnaire: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), Breast Cancer module (EORTC QLQ-BR23) and European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L) questionnaires
•Adverse events (AEs), including treatment-emergent AEs (TEAEs) and serious AEs (SAEs) according to NCT-CTCAE v4.03, including deaths
•Laboratory tests (hematology and biochemistry)
•Physical findings, 12-lead electrocardiogram (ECG) tests, ECOG performance status, and assessment of weight and vital signs

E.5.2.1

Timepoint(s) of evaluation of this end point

- Objective Response Rate (ORR) will be followed every 8 weeks until progression, an expected average of 18 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)

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

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

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

United States

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

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

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

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)

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

2020-11-20

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	Completed

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