Clinical Trials Register

Summary
EudraCT Number:	2018-003620-37
Sponsor's Protocol Code Number:	STH19580
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-10-31
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

UK - MHRA

A.2

EudraCT number

2018-003620-37

A.3

Full title of the trial

NEPTUNE: Enhancement of immuNothEraPy combining avelumab and repeaT doses of radiUm-223 in ER+ve, HER2-ve metastatic breast caNcEr.

A.3.1

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

Assessing the safety of avelumab with radium-223 in breast cancer patients with bone metastases.

A.3.2

Name or abbreviated title of the trial where available

NEPTUNE

A.4.1

Sponsor's protocol code number

STH19580

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	Sheffield Teaching Hospitals NHS Foundation Trust
B.1.3.4	Country	United Kingdom
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	Breast Cancer Now
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Pfizer Inc
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Bayer Healthcare Pharmaceuticals LLP
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinical Trials Research Unit, University of Leeds
B.5.2	Functional name of contact point	Jamie Oughton
B.5.3	Address:
B.5.3.1	Street Address	Clinical Trials Research Unit, Univeristy of Leeds
B.5.3.2	Town/ city	Leeds
B.5.3.3	Post code	LS2 9JT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01133431494
B.5.6	E-mail	medctnep@leeds.ac.uk

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	Germany
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	Xofigo
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Radium-223 dichloride
D.3.9.1	CAS number	444811-40-9
D.3.9.2	Current sponsor code	BAY 88-8223
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	KBq/Kg kilobecquerel(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1000 at ref date
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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.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	Bavencio
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Bavencio
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	IgG1 isotype
D.3.9.1	CAS number	1537032-82-8
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

ER+ve HER-ve breast cancer with bone metastases

E.1.1.1

Medical condition in easily understood language

Breast cancer that has spread to the bones

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	10006280
E.1.2	Term	Breast neoplasm benign female
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

Phase Ib: initial safety phase
• To determine whether avelumab can be safely combined with radium-223 in patients with ER+ve and HER2-ve metastatic breast cancer patients.

(ER+ve and HER2-ve are genetic characteristics that we know affect the likely response to treatment. Metastatic means that the cancer has spread to one or more other locations in the body)

Phase IIa: randomised expansion phase
• To assess whether the activity of avelumab immunotherapy in metastatic ER+ve HER2-ve breast cancer is enhanced by radium-223.

E.2.2

Secondary objectives of the trial

Secondary objectives
• To evaluate the longer-term safety and toxicity of the combination of radium-223 and avelumab in patients with ER+ve, HER2-ve metastatic breast cancer
• To further evaluate the efficacy of the combination in terms of additional measures of anti-tumour activity.
• To evaluate the effect of the combination of radium-223 and avelumab on bone turnover markers (PINP and uNTX:creatinine ratio).
• To evaluate time to first symptomatic skeletal-related event (SSE).
• To evaluate time to progression of bone disease and time to first documented disease progression (clinical or radiological).
• To evaluate quality of life in patients with ER+ve and HER2-ve metastatic breast cancer
(efficacy is the ability to produce the desired effect, toxicity is a measure of unwanted effects of treatment (eg fever, seizure), examples of symptomatic skeletal-related events are fractures or severe bone pain, quality of life will be measure using participant questionnaires)

Exploratory t

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Female patients >=18 years, with histological evidence of ER+ve, HER2-ve primary breast cancer
2. Radiological evidence of bone metastasis (with or without metastasis at other sites) to include plain radiograph, bone scan, CT or MRI and assessed according to RECIST v1.1, with at least 2 bone metastatic lesions on screening investigations performed at least 6 weeks prior to confirmation of eligibility
3. Measurable disease by RECIST 1.1 (including bone scans – see above)
4. 2-5 prior chemotherapy treatments for advanced disease, including an anthracycline and a taxane, unless contraindicated or patient has declined previous treatment or alternative treatment.
5. ECOG Performance Status 0, 1 or 2.
6. Life expectancy >6 months
7. Adequate haematological, renal and hepatic function and bone marrow function. Laboratory requirements within 14 days prior to confirmation of eligibility and start of trial treatment as follows;
a. Neutrophil count ≥1.5 x10^9/L
b. Platelet count ≥100 x10^9/L
c. Haemoglobin ≥9.0 g/dL
d. Total bilirubin level ≤1.5 xULN in treating institution (or ≤3.0 xULN for patients with Gilbert’s syndrome)
e. AST or ALT ≤3 xULN in treating institution
f. Calculated creatinine clearance or estimated GFR >40mls/min (Cockcroft and Gault or Wright formula may be used according to local practice)
8. Patient on bone targeted therapy (e.g. bisphosphonates or denosumab) for >6 weeks before confirmation of eligibility and starting treatment. No change to bone targeted therapy anticipated during study
9. Able to provide an archival primary tumour biopsy for assay of PD-1 expression (Please note that for Phase IIa participants only, provision of a biopsy from a metastatic lesion if already available, or optional provision of a new metastatic biopsy)
10. Patient must be fully informed about the study and has signed the informed consent form.
11. Patient must be willing and able to comply with the protocol, have mental capacity and (if relevant) use effective contraception throughout treatment and for 6 months after treatment completion.

E.4

Principal exclusion criteria

1. Presence of other currently active (diagnosis within the last 5 years) malignancy (except treated non-melanoma skin cancer (basal or squamous), carcinoma in situ of cervix and superficial bladder cancers).
2. External beam radiotherapy within 4 weeks of confirmation of eligibility and starting treatment.
3. Past medical history of autoimmune disorders or organ transplant including but not limited to myasthenia gravis,myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, poorly controlled type 1 diabetes, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
4. Previous treatment with immune checkpoint inhibitors
5. Active hepatitis B or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. Testing must be performed within 12 months prior to confirmation of eligibility.
6. HIV positive tested within 12 months prior to confirmation of eligibility.
7. Active tuberculosis based on clinical findings.
8. Receipt of an active live vaccine within 4 weeks of confirmation of eligibility and starting treatment.
9. Treatment with systemic immune stimulants or suppressors (including systemic steroids) within 2 weeks of confirmation of eligibility and starting treatment.
10. Requirement for ongoing steroids in the context of active/symptomatic brain/leptomeningeal metastases.
11. Presence of imminent or established spinal cord compression based on clinical findings and/or MRI
12. Known history of clinically significant cardiac disease as documented in the medical records
13. Positive pregnancy test at eligibility assessment for women of childbearing potential or breast-feeding women
14. Known hypersensitivity to any of the excipients of avelumab or radium-223 as documented in the medical records
15. Inability to tolerate antihistamine or antipyretic (e.g. paracetamol) as documented in the medical records
16. Coagulation dysfunction that is deemed by the investigator to be likely to interfere with trial treatment as identified by clotting panel (APTT and INR) within 12 months prior to confirmation of eligibility.
17. Thyroid dysfunction that is deemed by the investigator to be likely to interfere with trial treatment as identified by TSH, free T3 and free T4 within 6 months prior to confirmation of eligibility. Patients with a history of autoimmune-mediated hypothyroidism on a stable dose of thyroid replacement hormone are eligible.
18. Erythropoietin treatment within the 4 weeks prior to confirmation of eligibility and start of treatment

E.5 End points

E.5.1

Primary end point(s)

Phase Ib initial safety phase
The number of dose limiting toxicities (DLTs) observed during the DLT period. This will confirm the safety of radium-223 in combination with avelumab.

Randomised expansion phase
• Objective response rate (ORR) – this will be calculated as the proportion of participants achieving at least a partial response (according to RECIST 1.1 (to include bone response)) within 24 weeks of cycle 1 day 1.

E.5.1.1

Timepoint(s) of evaluation of this end point

DLTs: Evaluated during the safety phase by the Safety Review Committee after every cohort of 3 patients have been observed for the DLT period

Partial response: End of trial- when all patients have been followed up for at least 12 months
Overall response rate: End of trial- when all patients have been followed up for at least 12 months

E.5.2

Secondary end point(s)

Safety and toxicity as assessed by the occurrence of SAEs, SARs, SUSARs, ARs and AEs

Tumour response according to RECISTS 1.1 and where appropriate immune-RECIST, including maximum objective response of measurable non-osseous lesions, assessed within 24 weeks of cycle 1 day 1

Time to progression of bone disease, based on either unequivocal progression of existing bone lesion(s) or appearance of one or more new osteolytic bone lesions

Time to first documented disease progression either clinical or radiological

Disease control rate and duration of clinical benefit

Treatment compliance as assessed by dose omissions/delays

Change in bone turnover markers in serum (PINP) and urine (uNTX:creatinine ratio) from baseline to prior to cycle 4

Time to occurrence of first SSE

Quality of life as measured using EORTC QLQ-C30 and QLQ-BM22

E.5.2.1

Timepoint(s) of evaluation of this end point

End of trial- when all patients have been followed up for at least 12 months

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

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

PhIb and PhIIa

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

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

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 end of the trial will be defined as the date of the last participant’s last data item.

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