Clinical Trials Register

Summary
EudraCT Number:	2017-001755-31
Sponsor's Protocol Code Number:	NCT-2017-0417
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-03-22
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

Germany - BfArM

A.2

EudraCT number

2017-001755-31

A.3

Full title of the trial

Randomized Phase-II Study of Trabectedin/Olaparib Compared to Physician’s Choice in Subjects with Previously Treated Advanced or Recurrent Solid Tumors Harboring DNA Repair Deficiencies

Randomisierte Phase 2-Studie mit Trabectedin/Olaparib im Vergleich zu einer Behand-lung gemäß aktuellen onkologischen Therapieleitlinien bei Patienten mit bereits behandelten, lokal fortgeschrittenen oder wiederkehrenden metastasierten soliden Organtumoren bei molekulargenetisch nachgewiesener Störung der DNA-Reparatur

A.3.1

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

Study to Compare a Treatment with Trabectedin and Olaparib to Physician’s Choice in Subjects with Previously Treated Solid Tumors Having a Special lack of Cellular Repair Mechanism

Studie zu einer Behandlung mit Trabectedin und Olaparib im Vergleich zu Standardbehandlung nach ärztlichem Ermessen bei Patienten mit soliden Tumoren, die eine gestörte Zellreparatur haben.

A.3.2

Name or abbreviated title of the trial where available

NCT-PMO1603 TOP-ART

A.4.1

Sponsor's protocol code number

NCT-2017-0417

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03127215

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	Ruprecht-Karls-Universität Heidelberg, Medical Faculty
B.1.3.4	Country	Germany
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	DKFZ Heidelberg
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	AstraZeneca GmbH
B.4.2	Country	Germany
B.4.1	Name of organisation providing support	Pharma Mar S.A.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Heidelberg University Medical School
B.5.2	Functional name of contact point	Medical Oncology
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 460
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	+496221563521
B.5.5	Fax number	+496221565389
B.5.6	E-mail	richard.schlenk@nct-heidelberg.de

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	Yondelis
D.2.1.1.2	Name of the Marketing Authorisation holder	PharmaMar
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Trabectedin
D.3.2	Product code	ET-743
D.3.4	Pharmaceutical form	Powder for 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	TRABECTEDIN
D.3.9.1	CAS number	114899-77-3
D.3.9.4	EV Substance Code	SUB20756
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	1
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	Olaparib
D.3.4	Pharmaceutical form	Film-coated 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	Olaparib
D.3.9.1	CAS number	763113-22-0
D.3.9.2	Current sponsor code	AZD2281
D.3.9.3	Other descriptive name	OLAPARIB
D.3.9.4	EV Substance Code	SUB32234
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	150
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

Previously Treated Advanced or Recurrent Solid Tumors Harboring DNA Repair Deficiencies

Patienten mit lokal fortgeschrittenen bzw. metastasierten soliden Organtumoren bei molekulargenetisch nachgewiesenen Störungen im DNA-Reparaturweg

E.1.1.1

Medical condition in easily understood language

Previously Treated Advanced Tumors

Fortgeschrittene Krebserkrankung, die bereits behandelt wurde

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10065147
E.1.2	Term	Malignant solid tumor
E.1.2	System Organ Class	100000004864

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 assess clinical activity of combination therapy with trabectedin and olaparib in adult patients with advanced or recurrent solid tumors harboring DNA repair deficiency. Clinical efficacy is determined by disease control rate (DCR) at week 16

E.2.2

Secondary objectives of the trial

• To assess progression-free survival (PFS) of combination therapy with trabectedin and olaparib in comparison to treatment as per physician’s choice
• To assess overall survival (OS)
• To assess Tumor Response Rate (TRR) including CR and PR according RECIST v1.1 criteria after 16 weeks
• Safety/tolerability of combination therapy with trabectedin and olaparib
• Quality of life

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provision of a written informed consent
2. Patients is able to understand and comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
3. Progressive locally advanced or metastatic malignancy as determined by local investigator.
4. At least one measurable lesion that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment
5. Prior administration of at least one standard treatment for primary and/or relapsed malignancy according to current guidelines
6. Eastern Cooperative Oncology Group Performance Status ≤ 1
7. Patients with central venous access device in place (central venous catheter or port-a-cath)
8. Male or female patient aged ≥ 18 and ≤ 70 years
9. Postmenopausal or evidence of non-childbearing status. For women of childbearing potential: negative urine or serum pregnancy test within 14 days prior to study treatment and highly effective forms of contraception in place thereafter as well as confirmed negative urine or serum pregnancy test prior to treatment on day 1 of every cycle
Postmenopausal or evidence of non-childbearing status is defined as:
o Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
o Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50 except in patients with a history of surgical sterilisation (bilateral oophorectomy or hysterectomy)
o Radiation-induced oophorectomy with last menses >1 year ago
o Chemotherapy-induced menopause with >1 year interval since last menses
o Surgical sterilisation (bilateral oophorectomy or hysterectomy)
10. Female patients of child bearing potential and male patients with partners of child bearing potential, who are sexually active, must agree to the use of highly effective forms of contraception. This should be started from the signing of the informed consent and continue throughout period of taking study treatment and for 1 month (female patients) / 3 months (male patients) after last dose of study drug.
11. Identification of defective DNA repair via Homologous Recombination, as determined by molecular analysis within NCT/DKTK MASTER (Heidelberg Ethics Committee Reference No.: S-206/2011). Eligibility for the study is defined by the molecular tumorboard of NCT on the basis of whole-exome/genome sequencing and the presence of genomic markers for “BRCAness”.
12. Adequate bone marrow, renal, and hepatic function defined by laboratory tests within 14 days prior to study treatment:
o Hemoglobin ≥ 10 g/dl
o Neutrophil count ≥ 1,500/mm3
o Platelet count ≥ 100,000/µl
o Bilirubin ≤ 1.0 x upper limit of normal (ULN)
o ALT and AST ≤ 2.5 x ULN
o Alkaline phosphatase ≤ 2.5 x ULN
o PT-INR/PTT ≤ 1.5 x ULN
o Albumin ≥ 25 g/l
o Creatine kinase ≤ 2.5 x ULN
o Serum creatinine  1.5 mg/dl or creatinine clearance  51 ml/min (calculation according to Crockroft-Gault)

E.4

Principal exclusion criteria

1. Hematological malignancies and primary brain tumors. Patients with known progressive brain metastases determined by serial imaging or declining neurologic function in the opinion of the treating physician are not eligible. Patients with symptomatic uncontrolled brain metastases and patients with symptomatic uncontrolled spinal cord compression are not eligible. Patients with previously treated brain metastases are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the three months prior to enrollment. All patients with previously treated brain metastases must be clinically stable for at least 1 month after completion of treatment and off steroid treatment for one month, both prior to study enrollment
2. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years
3. Concurrent or previous treatment within 4 weeks in another interventional clinical trial
4. Treated with an investigational anticancer therapy less than 4 weeks prior to study treatment. Inclusion may be possible after > five half-lifes of previous treatment after consultation with the coordinating investigator on a case by case decision.
5. Prior treatment with PARP inhibitors
6. Patients with platinum-refractory disease, defined as progressive disease during or immediately after treatment with platinum based chemotherapy
7. Persistent toxicity (≥Grade 2 according to Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) caused by previous cancer therapy, excluding alopecia
8. Clinical signs of active infection (>Grade 2 according to CTCAE version 5.0)
9. History of HIV infection and immunocompromised patients
10. Viral active or chronic hepatitis (HBV or HCV)
11. Dementia or significant impairment of cognitive state
12. Epilepsy requiring pharmacologic treatment
13. Pregnancy and breast feeding (women)
14. Inability to take oral medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
15. Major surgery within 4 weeks of starting study treatment. Patients must have reco-vered from any effects of any major surgery.
16. Patients receiving any systemic chemotherapy or radiotherapy within 2 weeks prior to study treatment or a longer period depending on the defined characteristics of the agents used
17. Known hypersensitivity to any of the study drugs or other ingredients of the investigational medicinal products
18. Resting ECG with QTc > 450 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
19. Abnormal left ventricular ejection fraction, defined as ejection fraction of <50% on echocardiography
20. Heart failure NYHA III/IV
21. Severe obstructive or restrictive ventilation disorder
22. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is at least five half-lifes.
23. Concomitant use of known strong CYP3A inducers (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is at least five half-lifes (e.g. 5 weeks for enzalutamide or phenobarbital)

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoint is the disease control rate (DCR) at week 16

E.5.1.1

Timepoint(s) of evaluation of this end point

week 16 after five 21-days cycles of treatment in the experimental arm and either also after five 21-days cycles or alternatively four 28-days cycles in the physician’s choice arm

E.5.2

Secondary end point(s)

- Tumor response rate
- Survival analysis: Progression Free Survival, Overall Survival
- Safety analysis: frequency of adverse events
- Patient reportet outcomes including quality of life analysis

E.5.2.1

Timepoint(s) of evaluation of this end point

After treatment period (week 16) plus (optional) extended treatment period (until progression or End of Study) and safety follow-up (28 days).

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

Yes

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

Yes

E.8.1.6

Cross over

Yes

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

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

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 patient first visit plus 20 weeks

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

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

108

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)

None

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

2018-07-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-31

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-12-19

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