Clinical Trials Register

Summary
EudraCT Number:	2018-003249-41
Sponsor's Protocol Code Number:	M18DMB
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-11-16
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

Denmark - DHMA

A.2

EudraCT number

2018-003249-41

A.3

Full title of the trial

A multicentre phase IIa study to evaluate the efficacy and tolerability of ModraDoc006/r in patients with recurrent or metastatic HER-2 negative breast cancer, suitable for treatment with a taxane

A.3.1

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

A study in HER-2 negative metastatic breast cancer patients receiving ModraDoc006/r, an oral chemotherapy treatment regime of docetaxel

A.3.2

Name or abbreviated title of the trial where available

M18DMB

A.4.1

Sponsor's protocol code number

M18DMB

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	Modra Pharmaceuticals B.V.
B.1.3.4	Country	Netherlands
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	Modra Pharmaceuticals B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SMS-oncology
B.5.2	Functional name of contact point	regulatory@sms-oncology.com
B.5.3	Address:
B.5.3.1	Street Address	Walaardt Sacréstraat 401-403
B.5.3.2	Town/ city	Schiphol
B.5.3.3	Post code	1117 BM
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31204350580
B.5.5	Fax number	+31204350589
B.5.6	E-mail	regulatory@sms-oncology.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	ModraDoc006
D.3.2	Product code	ModraDoc006
D.3.4	Pharmaceutical form	Tablet
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	DOCETAXEL
D.3.9.1	CAS number	114977-28-5
D.3.9.2	Current sponsor code	ModraDoc006
D.3.9.3	Other descriptive name	ModraDoc006
D.3.9.4	EV Substance Code	SUB12492MIG
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	Yes
D.2.1.1.1	Trade name	Norvir
D.2.1.1.2	Name of the Marketing Authorisation holder	AbbVie Deutschland GmbH & Co. KG
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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.3.4	Pharmaceutical form	Tablet
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	RITONAVIR
D.3.9.1	CAS number	155213-67-5
D.3.9.4	EV Substance Code	SUB10342MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
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

recurrent/ metastatic HER-2 negative breast cancer, suitable for treatment with a taxane

E.1.1.1

Medical condition in easily understood language

recurrent/ metastatic breast cancer without or with very low level of HER-2 protein in the cancer cells

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	PT
E.1.2	Classification code	10006187
E.1.2	Term	Breast cancer
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 determine the efficacy of ModraDoc006/r (oral docetaxel formulation given as ModraDoc006 10 mg tablets in combination with ritonavir 100 mg tablets) as measured by RECIST v1.1 criteria of objective response rate (ORR) in patients with histologically and cytologically confirmed, recurrent or metastatic HER-2 negative breast cancer suitable for treatment with a taxane.

E.2.2

Secondary objectives of the trial

To assess safety and tolerability of ModraDoc006/r
To obtain activity data on progression-free survival (PFS) of ModraDoc006/r, according to RECIST v1.1 criteria

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Able to give written informed consent and to comply with the protocol
2. Histologically- or cytologically confirmed diagnosis of recurrent or metastatic HER-2 negative breast cancer
3. Female of age 18 years or above
4. Patients who are eligible to receive a taxane as monotherapy as 1st-3rd line of therapy for recurrent or metastatic breast cancer. A maximum of two previous lines of chemotherapy is allowed (including experimental i.e. non-registered chemotherapy alone or in combination). Re-treatment with one of the same drugs after treatment interruption for reasons of patient preference and/or progression of disease counts as a new treatment
5. WHO performance status of 0, 1 or 2 (Appendix II)
6. Estimated life expectancy of at least 12 weeks
7. Resolution of toxicity of prior therapy to < grade 2 (except for alopecia and transaminases in case of liver metastases) as defined by CTCAE v5.0
8. Evidence of measurable disease present at baseline as defined by RECIST v1.1
9. Able and willing to swallow oral medication
10. Able and willing to undergo radiologic scans (CT scan, or MRI if CT is contraindicated)
11. All patients of childbearing potential must have a negative high sensitive pregnancy test at screening (urine/serum) and agree to use highly effective method for contraception from time of signing Informed Consent until at least 12 weeks after the last administration of study drug
12. Laboratory criteria:
• Platelet count ≥ 100 x 109 /L
• Haemoglobin ≥ 6.0 mmol/L or 9.67 g/dL
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109 /L
• Total bilirubin ≤ 1.5 x ULN, except for patients with familial bilirubinaemia (Gilbert’s disease)
• Serum ASAT and ALAT ≤ 2.5 x ULN (≤ 5 x ULN with liver metastases)
• Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min (by Cockcroft-Gault formula or MDRD [Modification of Diet in Renal Disease])

E.4

Principal exclusion criteria

1. Systemic chemotherapy and radiation therapy within the last 4 weeks, endocrine based therapy and CDK4/6 inhibitors within 1 week prior to first dose of ModraDoc006/r. Single dose palliative radiation for pain relieve is allowed until one week prior to start with ModraDoc006/r (these lesions are not to be included as target lesions)
2. Any treatment with investigational drugs (or investigational device) within 21 days prior to receiving the first dose of ModraDoc006/r
3. Previous treatment with a taxane for recurrent or metastatic breast cancer
4. Major surgical procedures within 21 days prior to providing informed consent
5. Active acute or chronic infection, which is not controlled by appropriate medication (at the discretion of the treating physician)
6. Uncontrolled or significant cardiovascular disease defined as New York Heart Association Classification III or IV
7. Patients with known alcoholism, drug addiction and/or psychiatric of physiological condition which in the opinion of the Investigator would impair study compliance
8. Any medical condition that in the opinion of the Investigator would contra-indicate or preclude participation within the clinical trial, or would put the patient at high risk for treatment-related complications
9. Previous malignancies within the last three years other than breast carcinoma, except successfully treated squamous/basal cell carcinoma of the skin, superficial bladder cancer, and in situ carcinoma of the cervix
10. Patients with symptomatic brain metastases. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anticonvulsant therapy for at least 6 weeks are allowed to enrol. Radiotherapy for brain metastasis must have been completed at least 6 weeks prior to start of study treatment. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening, demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive anti-epileptic drugs or corticosteroid treatment indicated for brain metastasis
11. Patients with confirmed leptomeningeal metastases
12. Women who are pregnant or breast feeding
13. Known positivity for Human Immunodeficiency Virus HIV-1 or HIV-2 type
14. Patients with known active infection of hepatitis B, C, or E (patients who are anti-HBC positive but HBsAg negative are eligible to participate in this study)
15. Bowel obstructions or motility disorders that may influence the resorption of drugs as judged by the Investigator
16. Patients with unstable ascites, defined as need for palliative paracentesis or presence of a permanent peritoneal drain in the past 4 weeks prior to first dose of ModraDoc006/r. Enrolment in patients with peritonitis carcinomatosa and malignant ascites is allowed if there is no clinical and/or radiological known or suspected motility disorder within the 4 weeks prior to the first dose of ModraDoc006/r
17. Concomitant use of MDR, MRP, OATP1B1, OATP1B3 and CYP3A modulating drugs such as Ca+- entry blockers (verapamil, dihydropyridines), cyclosporine, quinidine, tamoxifen, megestrol and grapefruit juice, concomitant use of HIV medications, other protease inhibitors, (non) nucleoside analogues, or St. John’s wort (see section 5.8). These need to have been stopped at least 5 times half-life (according to Summary of Product Characteristics (SPC)) or 7 days, whichever is longest, in order to prevent interaction with the drug. Tamoxifen and megestrol need to be stopped only 1 week prior to start of the first dose of ModraDoc006/r
18. Legal incapacity

E.5 End points

E.5.1

Primary end point(s)

To determine objective response rate (ORR) according to RECIST v1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 8, week 12 and ongoing radiological scans every 6 weeks until disease progression (according to RECIST v1.1), unacceptable toxicity, or discontinuation for any other reason.

E.5.2

Secondary end point(s)

1 To assess progression-free survival (PFS)
2 To assess (serious) adverse events (SAEs) according to the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0
3 To evaluate safety assessments of e.g.: physical examinations, body weight, vital signs, WHO performance status, changes in haematology and biochemistry, electrocardiogram (ECG)

E.5.2.1

Timepoint(s) of evaluation of this end point

1 PFS: Screening, Week 8, week 12 , thereafter in 6-week intervals while on study treatment and at EOT
2 SAEs: day 1, day 8 and day 15 of Cycle 1 & 2, every 2 weeks after Cycle 2, EoT and at 30-day FU
3 assessments (physical examinations, body weight, vital signs, WHO performance status, changes in haematology and biochemistry): screening, day 1, day 8 and day 15 of Cycle 1 & 2, every 2 weeks after Cycle 2, EoT and at 30-day FU
3 assessments (ECG): Screening, week 6 and EoT

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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 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:

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

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

Frailty patients by means of two validated screening tools (SPPB and G8 questionnaire)

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)

After patients have stopped study medication due to disease progression, unacceptable toxicity, study finalization, or for discontinuation for any other reason, further treatment will be decided by their treating oncologist.There will be no compassionate use of study medication.

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

2019-01-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-12-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-11-09

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