Clinical Trials Register

Summary
EudraCT Number:	2018-002944-10
Sponsor's Protocol Code Number:	c16174
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2018-11-20
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

Netherlands - Competent Authority

A.2

EudraCT number

2018-002944-10

A.3

Full title of the trial

Phase III Trial of Docetaxel vs. Docetaxel and Radium-223 for Metastatic Castration-Resistant Prostate Cancer (mCRPC)

A.3.1

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

Trial comparing subjects with Metastatic Castration-Resistant Prostate Cancer (mCRPC) treated with Docetaxel vs. subjects treated with a combination of Docetaxel and Radium-223

A.3.2

Name or abbreviated title of the trial where available

Dora trial

A.4.1

Sponsor's protocol code number

c16174

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03574571

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	Memorial Sloan Kettering Cancer Center
B.1.3.4	Country	United States
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	Bayer Healthcare LLC
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Siron bv
B.5.2	Functional name of contact point	CEO
B.5.3	Address:
B.5.3.1	Street Address	Brugstraat 44a
B.5.3.2	Town/ city	Roosendaal
B.5.3.3	Post code	4701LJ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31652511287
B.5.6	E-mail	info@sironclinical.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	Xofigo
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
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.3.4	Pharmaceutical form	Solution for injection
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	Yes
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

Patients with histological or cytological proof of Metastatic Castration-Resistant Prostate Cancer (mCRPC)

E.1.1.1

Medical condition in easily understood language

Advanced prostate cancer with bone metastases

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Compare overall survival for subjects treated with docetaxel versus subjects treated with docetaxel plus raduim-223

E.2.2

Secondary objectives of the trial

To compare:
a. Radiographic progression free survival as defined in PCWG3 criteria;
b. Symptomatic Skeletal event free survival;
c. Time to total alkaline phosphatase (ALP) progression;
d.On-treatment alterations in quality of life as assessed by FACT-P, BPI, and BFI measures between subjects who receive docetaxel with those who receive docetaxel and radium-223.
To determine if there is excessive:
e. Febrile neutropenia in subjects treated with docetaxel plus radium-223;
f. Treatment discontinuation in subjects who are on their fourth line of therapy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria:
•Willing and able to provide, or have a legally authorized representative provide, written informed consent (ICF) and HIPAA authorization for the release of personal health information. A signed informed consent must be obtained before screening procedures are performed.

NOTE: HIPAA authorization may be either included in the informed consent or obtained separately.
•Males 18 years of age and above
•Histological or cytological proof of prostate cancer

•Documented progressive mCRPC based on at least one of the following criteria:
1.a) PSA progression defined as a minimum of 2 rising PSA levels with a minimum of a 1 week interval between each determination. A minimum PSA of 1.0 ng/mL is required for study entry.
2.Soft-tissue progression defined as an increase ≥ 20% in the sum of the LD of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions.
3.Progression of bone disease (evaluable disease) or two or more new bone lesions by bone scan.

•Two or more bone lesions defined by nuclear bone scan
•ECOG 0- 1

•Normal organ function with acceptable initial laboratory values within 14 days of randomization:
◦Albumin > 30 g/L
◦ANC ≥ 1.5 x 10^9/L
◦Hemoglobin ≥ 10 g/dL
◦Platelet count ≥ 100 x 10^9/L
◦Creatinine ≤ 1.5 x the institutional upper limit of normal (ULN)
◦Bilirubin ≤ ULN (unless documented Gilbert's disease)
◦SGOT (AST) ≤ 1.5 x ULN
◦SGPT (ALT) ≤ 1.5 x ULN
◦WBC count ≥ 3 x 10^9/L

•3.1.8 Subjects must agree to use a medically acceptable method of birth control (e.g., spermicide in conjunction with a barrier such as a condom) or sexual abstinence for the duration of the study, including 6 months after the last dose of study drug. Sperm donation is prohibited during the study and for 6 months after the last dose of study drug. Female partners must use hormonal or barrier contraception unless postmenopausal or abstinent.
•Serum testosterone < 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH analogue (agonist or antagonist) if they have not undergone orchiectomy.
•All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1 or less.
•Willing and able to comply with the protocol, including follow-up visits and examinations.

E.4

Principal exclusion criteria

Exclusion Criteria:
•3.2.1 Received any other investigational therapeutic agents or other anticancer therapies within 2 weeks or 5 half-lives, whichever is shorter, prior to randomization.
•Received external beam radiotherapy within the 2 weeks prior to randomization.
•Has an immediate need for external beam radiotherapy.
•Has received any other systemic investigational or anti-cancer radiopharmaceutical in the past.
•Has received any prostate cancer directed chemotherapy in the castration resistant setting.
•Has received > 6 prior doses of docetaxel in the castration sensitive setting. Subjects who have received up to 6 prior doses of docetaxel in the castration sensitive setting are permitted if they have not experienced disease progression within 36 weeks of last treatment with docetaxel.
•Has received four or more systemic anticancer regimens for mCRPC.
◦Treatment with docetaxel or abiraterone for non-castrate metastatic disease is permissible and does not count towards the lines of therapy for mCRPC
◦A 'line' is a regimen. Combinations of hormones and other types of therapies count as single lines.

•Has known Grade ≥3 non-hematological docetaxel related toxicities or docetaxel toxicity related dose interruption or discontinuation.
•Has received blood transfusions or growth factors within the last 4 weeks prior to randomization.
•Symptomatic nodal disease (i.e., scrotal, penile, or leg edema).
•Has visceral metastases with ≥ 3 lung and/or liver metastases or individual lesion ≥2 cm, as assessed by CT scan or MRI of the chest/abdomen/pelvis within the last 8 weeks prior to randomization.
•Symptomatic loco-regional disease that causes ongoing Grade 3 or Grade 4 urinary or rectal symptoms.
•Subjects with a second malignancy with a risk of recurrence >30% within the next 3 years. Non-melanoma skin cancers, non-invasive bladder cancers, and other in-situ or non-invasive malignancies are permitted while on study.
•Has imminent or established cord compression based on clinical findings and/or MRI.
•Known bone marrow dysplasia
•Has received any of the following in the 4 weeks prior to randomization: 5-alpha-reductase inhibitors, herbal medications, natural hormonally active foods (e.g., phytoestrogens) or other food supplements known to alter PSA in humans
•Is receiving ongoing treatment with herbal medications that are known in humans to alter PSA or the natural history of prostate cancer. Subjects must discontinue any such herbal medications prior to the first dose of study drug
•Any other serious illness or medical condition that would, in the opinion of the investigator, make this protocol unreasonably hazardous, including but not limited to:
◦Uncontrolled infection
◦NYHA III or IV heart failure
◦Crohn's disease or those with ulcerative colitis who have not undergone a colectomy
◦Known active infection with HIV, Hepatitis B or Hepatitis C

E.5 End points

E.5.1

Primary end point(s)

primary endpoint
The overall survival comparison between treatments will be evaluated at each interim analysis and the final analysis using the stratified logrank test. The stratification factors are:
1. Prior docetaxel for castrationsensitive disease (Yes or No)
2. Visceral disease (presence or absence)

E.5.1.1

Timepoint(s) of evaluation of this end point

At each interim analysis and the final analysis

E.5.2

Secondary end point(s)

secondary and correlative endpoints
· • Time to event endpoints will be analyzed using a stratified log-rank test with the same stratification factors. Kaplan-Meier estimates of symptomatic skeletal event-free survival and radiographic PFS will be computed. The cumulative incidence function will be used to compute probabilities for the time to first skeletal related event and the time to ALP progression. All time to event probability estimates will be calculated within treatment.
· tALP response will be compared between the treatment groups using a CMH test adjusting for the randomization strata.
· Time to maximum % post-therapy decrease in PSA will be summarized using descriptive statistics
· Maximum % decrease in PSA will be summarized using descriptive statistics (e.g., mean, standard deviation, median, minimum, and maximum)
· Longitudinal kernel smoothing methods will be used to estimate the PSA, bone marker, BSI, CTC, and ctDNA trajectories over time. Joint modeling will used to evaluate these trajectories with respect to overall survival.
· • PROs will include scores from the QOL questionnaires: FACT-P, BPI, and BFI. The QOLs will be administered at baseline, week 19, safety follow up, and follow up visits every 3 months for 1 year from last dose of either study drug. The score-specific area under the curve (with respect to time) will be derived for each subject and these area-under-curve (AUCs) will be compared between treatments. To account for potential subject withdrawal, the Mann-Whitney U-statistic will be used for the comparison; where for each pair of subjects (one from each treatment) the AUCs are based on the minimum follow-up time. In addition, a linear mixed effects model will be employed to evaluate the effect of treatment on QOL scores after adjusting for potential confounding factors.
· The number and percentage of febrile neutropenia in subjects treated with docetaxel plus radium-223
· The percentage of treatment discontinuation in subjects who are on their fourth line of therapy will be calculated by treatment arm and total.

E.5.2.1

Timepoint(s) of evaluation of this end point

All time to event probability estimates will be calculated within treatment.

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)

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

no treatment (Docetaxel plus Radium is compared to Docetaxel alone)

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

Brazil

United States

Netherlands

Spain

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

The last visit of the last subject undergoing the trial

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:

148

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

590

F.2 Gender

F.2.1

Female

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

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

F.4 Planned number of subjects to be included

F.4.1

In the member state

250

F.4.2

For a multinational trial

F.4.2.1

In the EEA

300

F.4.2.2

In the whole clinical trial

738

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)

Not different from the expected normal treatment of that condition

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Stichting DUOS
G.4.3.4	Network Country	Netherlands

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-11-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-27

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
Orphan Designation Number:
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