Supplement: ALSYMPCA (BC1-06) Study Protocol and Statistical Analysis Plan

(1)

This supplement contains the following items:

1. Final ALSYMPCA (BC1-06) Clinical Study Protocol 2. Protocol Amendments – Amendment 1 Final – Amendment 2 Final – Amendment 3 Final – Amendment 4 Final – Amendment 5 Final – Amendment 6 Final 3. Statistical Analysis Plan

– ALSYMPCA (BC1-06) SAP Final

(2)

(3)

Principal Investigator:

Christopher Parker, M.D., Consultant Oncologist Tel: +44 (0) 208 661 3425

E-mail: [email protected]

The Royal Marsden Hospital

Downs Road, Sutton, Surrey SM2 5PT, UK Switchboard: +44 (0) 208 661 6011

Fax: +44 (0) 208 643 8809

SPONSOR PERSONNEL: Address

Sponsor Contact Person

Karin Staudacher

Director Clinical Research

Tel:+47 23 00 78 10, Mobil: +47 45 20 26 32 E-mail: [email protected] Algeta ASA P.O.Box 54 Kjelsås, N-0411 Oslo, Norway Switchboard: +47 23 00 79 90 Fax: +47 23 00 79 91

Drug Safety Officer

Ingvild Haugen

Director Clinical Research/Drug Safety Officer Tel: + 47 23 00 78 14, Mobile: +47 91 17 89 31 E-mail: [email protected]

COLLABORATORS: Address

CRO Contact Persons

Manuela Niewel (medical monitor worldwide except Brazil, Canada, US):

Dr. Med. Manuela Niewel

Senior Medical Director Oncology Phone: +49 8193 9371 442 Fax: +49 8193 9371 443 Mobile: +49 173 6793 683 E-Mail: [email protected] CRO-PharmaNet Services GmbH Frankfurter Strasse 233 D-63263 Neu-Isenburg Germany

Gary Fishbein (medical monitor for Brazil, Canada, US):

Dr Gary Fishbein, Senior Medical Director Phone: +1 215 591 7369

Mobile: +1 609 933 2844 Fax: +1 609 720 5271

Email: [email protected]

After hours urgency call centre: +1 609 951 6800

Safety Desk: Principal contact: Jo Williams

Manager, Global Safety & Pharmacovigilance Phone: + 44 1494 560 524

Safety fax number: + 44 1494 896227 Email: [email protected]

PharmaNet Limited Buckingham Court Kingsmead Business Park High Wycombe

Bucks HP11 1JU United Kingdom

Phone: + 44 1494 896240 (switchboard)

(4)

1 PROTOCOL SYNOPSIS

Name of sponsor/company: Algeta ASA, Oslo, Norway

Name of Drug Product: Alpharadin® Injection (radium-223)

Name of Drug Substance: Radium-223 chloride

Title of Study:

A double-blind, randomised, multiple dose, Phase III, multicentre study of Alpharadin in the treatment of patients with symptomatic hormone refractory prostate cancer with skeletal metastases.

Study Centre(s):

Estimated about 155 centres world-wide

Phase of Development: III

Primary Objective:

To compare, in patients with symptomatic hormone refractory prostate cancer (HRPC) and skeletal metastases, the efficacy of best standard of care plus Alpharadin versus best standard of care plus placebo, with the primary efficacy endpoint being overall survival (OS).

Secondary Objectives:

To compare, in patients with symptomatic HRPC and skeletal metastases receiving either best standard of care plus Alpharadin versus best standard of care plus placebo:

• Time to occurrence of specified disease events

• Changes and time to progression in serum PSA and total ALP concentrations • The acute and long term safety profile

• Quality of life • Health economics

Study Design:

This is a double-blind, randomised, multiple dose, placebo-controlled, international Phase III pivotal efficacy and safety study of Alpharadin.

Patients will participate in two study periods:

• Treatment period: from first injection of Alpharadin or placebo, to 4 weeks after last injection of Alpharadin or placebo, normally 24 weeks. The study treatment consists of 6 intravenous

administrations of Alpharadin or placebo (normal saline) each separated by an interval of 4 weeks. Prior to each study treatment, samples will be assessed to ensure an adequate haematology profile. Other treatments for prostate cancer should be used in accordance with routine clinical practice, at the discretion of the Investigator. If cytotoxic chemotherapy, other systemic radioisotopes or hemibody external radiotherapy treatments are considered as the best standard of care to be given during the treatment period, further study drug administrations must be discontinued.

• Follow-up period: from 4 weeks after last administration of study drug until 3 years from first administration, thereafter collection of date of death until the last patient has been followed for 3 years. Patients will be evaluated every 2 months until 1 year after first administration, and thereafter every 4 months until 3 years from first administration. Date of death will be collected for all patients until the last patient has been followed for 3 years. Patient management will be in accordance with routine clinical practice, at the discretion of the Investigator.

At the time of issuance protocol version 6, the interim analysis described in the Protocol Section 12 has been performed, and the Independent Data Monitoring Committee (IDMC) has confirmed that the results met the pre-defined criteria and recommended to conclude and unblind the study. The sponsor has decided to follow the recommendation from the IDMC.

On this basis, the study will be unblinded and the investigators informed about the treatment allocation for their patients. Investigators will be allowed to offer placebo patients who are still participating in the study (i.e. have not withdrawn from the study) and who fulfil the eligibility criteria as defined in this protocol

(5)

addendum, a full course of Alpharadin treatment (50 kBq/kg body weight (b.w.) administered 6 times, at intervals of 4 weeks). The placebo patients entering into a new treatment period with Alpharadin will be followed up as described in the protocol and this protocol addendum, until the last patient of the original patient population has been followed up for 3 years.

A separate protocol addendum describes the study procedures for the placebo patients who are offered Alpharadin treatment.

There are no changes to the treatment and follow-up of the patients who have already received Alpharadin before unblinding of the study or of the patients who have received placebo before unblinding but who do not enter into treatment with Alpharadin. These patients will continue follow up as previously planned in the protocol.

Patient Population:

The target population is patients with progressive symptomatic HRPC, with at least two skeletal metastases on bone scan and no known visceral metastases.

Specifically the target population is

o Patients who have received docetaxel

o Patients who are not fit enough to receive docetaxel

o Patients not willing to receive docetaxel,

o Patients for whom docetaxel is not available for other reasons

“Symptomatic” is defined as either regular (not occasional) use of analgesic medication for cancer related bone pain (≥ level 1; WHO ladder for cancer pain), or treatment with EBRT for bone pain (the EBRT should be within the last 12 weeks before randomisation).

“Best standard of care” is regarded as the routine standard of care at each centre, for example local external beam radiotherapy, corticosteroids, antiandrogens, oestrogens (e.g. stilboestrol), estramustine or ketoconazole.

The screening haematology values are recommended to be measured at a maximum of 1 week prior to randomisation and the first injection should be done as soon as possible after randomisation.

PSA progression has to be documented by 2 consecutive rises in PSA over a previous reference value within 6 months prior to randomisation (thus, reference value < progression value 1 < progression value 2). The progression values should be at least one week apart. It is accepted that after the documented PSA progression, the PSA could decline prior to randomisation, provided that the screening value is at least 5ng/ml.

Sample Size:

A total of approximately 900 patients will be randomised in a 2:1 allocation ratio (Alpharadin:Placebo).

Inclusion Criteria:

1. Histologically or cytologicallyconfirmedadenocarcinoma of the prostate 2. Known hormone refractory disease defined as:

• Castrate serum testosterone level: ≤ 50 ng/dL (1.7 nmol/L)

• Bilateral orchiectomy or maintenance on androgen ablation therapy with LHRH agonist or polyestradiol phosphate throughout the study

• Serum PSA progression defined as two consecutive increases in PSA over a previous reference value, each measurement at least 1 week apart

3. Serum PSA value ≥ 5 ng/mL (µg/L)

4. Multiple skeletal metastases (≥ 2 hot spots) on bone scintigraphy within previous 12 weeks 5. No intention to use cytotoxic chemotherapy within the next 6 months

6. Either regular (not occasional) analgesic medication use for cancer related bone pain or treatment with EBRT for bone pain within previous 12 weeks

7. Age ≥ 18 years

8. ECOG Performance status (PS): 0-2 9. Life expectancy ≥ 6 months

(6)

a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L b. Platelet count ≥ 100 x109/L

c. Hemoglobin ≥ 10.0 g/dL (100 g/L; 6.2 mmol/L)

d. Total bilirubin level ≤ 1.5 institutional upper limit of normal (ULN) e. ASAT and ALAT ≤ 2.5 ULN

f. Creatinine ≤ 1.5 ULN g. Albumin >25 g/L

11. Willing and able to comply with the protocol, including follow-up visits and examinations 12. Must be fully informed about the study and signed the informed consent form

Exclusion Criteria

1. Treatment with an investigational drug within previous 4 weeks, or planned during the treatment period 2. Eligible for first course of docetaxel, i.e. patients who are fit enough, willing and where docetaxel is

available

3. Treatment with cytotoxic chemotherapy within previous 4 weeks, or planned during the treatment period, or failure to recover from adverse events due to cytotoxic chemotherapy administered more than 4 weeks ago (however ongoing neuropathy is permitted)

4. Prior hemibody external radiotherapy

5. Systemic radiotherapy with strontium-89, samarium-153, rhenium-186orrhenium-188 for the treatment of bony metastases within previous 24 weeks

6. Prior treatment with radium-223

7. Blood transfusion or erythropoetin stimulating agents within previous 4 weeks

8. Other malignancy treated within the last 5 years (except non-melanoma skin cancer or low-grade superficial bladder cancer)

9. History of visceral metastasis, or visceral metastases as assessed by abdominal/pelvic CT or chest x-ray within previous 8 weeks1

10. Malignant lymphadenopathy exceeding 3 cm in short-axis diameter

11. Imminent or established spinal cord compression based on clinical findings and/or MRI 12. Any other serious illness or medical condition such as, but not limited to:

 any uncontrolled infection  cardiac failure NYHA III or IV  Crohn’s disease or Ulcerative colitis  Bone marrow dysplasia

13. Unmanageable faecal incontinence

Investigational Product, Dose and Mode of Administration:

Alpharadin (radium-223) will be supplied in vials containing a ready to use solution. It will be administered intravenously as a slow bolus. The dose (administered radioactivity) will be 50 kBq/kg body weight (b.w.) and this dose will be administered 6 times, at intervals of 4 weeks.

Reference Therapy, Dose and Mode of Administration:

Saline solution of isotonic saline, administered intravenously as a slow bolus 6 times, at intervals of 4 weeks. Protocol version 6 implements a change to unblind the study based on the results of the interim analysis described in the Protocol Section 12. Following unblinding, no patients will receive placebo treatment.

Treatment Modifications:

• Study drug dose level adjustment is not permitted.

• Treatment intervals: Every effort should be made to keep the exact treatment interval of 4 weeks. • Adverse events: If the treatment needs to be delayed due to an adverse event study drug

administration can be delayed up to 4 weeks for recovery.

o Haematologic toxicity must resolve to CTCAE grade 2 or better prior to administration of next dose. In the absence of recovery after 4 weeks, patients are to discontinue further study drug administrations.

o Non-haematological toxicities must resolve to CTCAE grade 2 (gastrointestinal events) or grade 3 (other toxicity) prior to administration of next dose..

o Spinal cord compression during treatment phase: Study drug administration can continue

1

Abdominal/pelvic MRI will be accepted in place of abdominal/pelvic CT. CT covering the chest area will be accepted in place of chest x-ray.

(7)

after up to 4 weeks delay if the patient is adequately treated.

o Bone fracture: for traumatic fracture in weight bearing bones during treatment phase, the study drug administration should be delayed 2-4 weeks from fracture.

Concomitant Prostate Cancer Therapy:

• Patients receiving bisphosphonates prior to randomisation may be maintained on bisphosphonate therapy throughout all or part of the study. The bisphosphonate may be stopped or started at the discretion of the Investigator throughout the study (i.e., both treatment phase and follow-up). Injection of bisphosphonates should be done at least 2 hours before or after study drug administration.

• Patients who have not undergone bilateral orchiectomy are to receive LHRH agonists orpolyoestradiol phosphate throughout the study (i.e., both treatment phase and follow-up).

• Cytotoxic chemotherapy, other systemic radioisotopes and hemibody external radiotherapy or other investigational drugs should not be used during the treatment period. If such treatments are considered to be the best standard of care during the treatment period, further study drug administrations must be discontinued and treatment must not be given until at least 4 weeks after last study drug administration, if possible.

• Other concomitant treatments such as analgesia, EBRT, corticosteroids, oestrogens (e.g., stilboestrol), bisphosphonates, estramustine, ketoconazole, antiandrogens are permitted throughout the study according to routine clinical practice at the discretion of the Investigator.

• Blood transfusion or erythropoietin stimulating agents are allowed throughout the study after randomisation.

Duration of Study for a Single Patient:

Patients will receive 6 administrations of study drug every 4 weeks in the absence of any treatment discontinuation criteria, as follows:

• Unacceptable toxicity defined as:

o CTCAE grade 3-4 neutropenia or thrombocytopenia lasting > 14 days

o CTCAE grade 4 non-haematological toxicity lasting > 7 days despite adequate treatment • Initiation of cytotoxic chemotherapy, other systemic radioisotopes, hemibody external radiotherapy

or other investigational drug

Subsequently, during the follow-up period the patients will be evaluated every 2 months until 1 year from first administration, and thereafter every 4 months until 3 years from first administration.

If patients discontinue treatment they will have a discontinuation visit 4 weeks after the last injection. They will then enter the follow-up phase including all remaining follow-up visits throughout the entire follow-up period. If the patient is withdrawn from the study (will not return for any more visits) during the treatment period, the patient should be encouraged to come to a safety follow up visit 4 weeks after last treatment visit.

Endpoints:

Primary efficacy endpoint

Overall survival: time from date of randomisation to the date of death

Secondary efficacy endpoints Main secondary efficacy endpoints

• Time to total-ALP progression

• Total-ALP progression is defined

i. in patients with no total-ALP decline from baseline as: ≥ 25% increase from the baseline value, at least 12 weeks from baseline

ii. in patients with an initial total-ALP decline from baseline as: ≥ 25% increase above the nadir value, which is confirmed by a second value obtained three or more weeks later.

• Total-ALP response defined as:

• Confirmed total-ALP response: ≥30% reduction of the blood level, compared to the baseline value, confirmed by a second total-ALP value approximately 4 or more weeks later.

• Time to occurrence of first skeletal related event.

• A skeletal related event is the use of external beam radiotherapy to relieve skeletal symptoms or the occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral) or the occurrence of spinal cord compression or a tumour related orthopaedic surgical intervention.

(8)

• Total-ALP normalisation

• Defined as the return of total-ALP value to within normal rangeat 12 weeks in 2 consecutive measurements (at least 2 weeks apart) after start of treatment in patients who have their ALP above ULN at baseline.

• Time to PSA progression

• PSA progression is defined

i. in patients with no PSA decline from baseline as: ≥ 25% increase from the baseline value and an increase in absolute value of ≥ 2 ng/mL, at least 12 weeks from baseline ii. in patients with an initial PSA decline from baseline as: ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir value, which is confirmed by a second value obtained three or more weeks later

Other secondary efficacy endpoints

• Time to occurrence of first use of external beam radiotherapy to relieve skeletal symptoms • Time to occurrence of first use of radio-isotopes to relieve skeletal symptoms

• Time to occurrence of first new symptomatic pathological bone fractures (vertebral and non-vertebral) • Time to occurrence of first tumour related orthopaedic surgical intervention

• Time to occurrence of first spinal cord compression

• Time to occurrence of first start of any other anti-cancer treatment

• Time to occurrence of first deterioration of ECOG PS by at least two points from baseline [includes death (score of 5), by definition].

• Changes in PSA

• PSA response will be derived, defined as:

• ≥30% reduction of the blood level, compared to the baseline value • ≥50% reduction of the blood level, compared to the baseline value

• Confirmed PSA response: ≥50% reduction of the blood level, compared to the baseline value, confirmed by a second PSA value approximately 4 or more weeks later

• Changes in total-ALP

• Total-ALP response will be derived, defined as:

• ≥50% reduction of the blood level, compared to the baseline value

• Confirmed total-ALP response: ≥50% reduction of the blood level, compared to the baseline value, confirmed by a second total-ALP value approximately 4 or more weeks later

Safety endpoints

• Incidence and severity of adverse events and laboratory abnormalities, graded according to the National Cancer Institute – Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0

• Incidence of Serious Adverse Events (SAE)

• Incidence of treatment discontinuations due to adverse events

• Incidence of potential manifestations of late toxicity, such as new primary cancers and bone marrow changes (acute myelogenous leukaemia, myelodysplastic syndrome and aplastic anaemia)

Clinical benefit endpoints

• Performance status (PS) response and progression defined as:

o at least a 1-point improvement or worsening, respectively, on the ECOG scale from baseline value

• Quality of life (QoL) assessed using:

o Functional Assessment of Cancer Therapy - Prostate (FACT-P) questionnaire

o EuroQoL (EQ-5D) which will also be included in the health economics analysis The QoL forms may be used only in those countries where the forms are translated and validated.

Health economics

A health economic analysis of the treatment is being planned in some countries. Cost data will be collected from each hospital and utilized in an economic model. Efficacy, QoL in the form of Quality-Adjusted Life-Years (QALYs), life-years gained and other data collected in this study may be used as inputs to the model.

Sample Size:

(9)

The sample size calculation is based on the following assumptions: • Two-sided Type I error: 5%

• Power: 90%

• Treatment allocation ratio: 2:1 (Alpharadin:placebo) • 50% of patients have had prior docetaxel treatment

• Median survival time in the placebo arm - no prior docetaxel treatment: 18 months • Median survival time in the Alpharadin arm - no prior docetaxel treatment: 22 months • Median survival time in the placebo arm - prior docetaxel treatment: 12 months • Median survival time in the Alpharadin arm - prior docetaxel treatment: 15 months • Common hazard during the first 4 months: 1.4 %

• Hazard in Alpharadin arm after 4 months – no prior docetaxel treatment: 3.6 % • Hazard in placebo arm after 4 months – no prior docetaxel treatment: 4.5 % • Hazard in Alpharadin arm after 4 months – prior docetaxel treatment: 5.8 % • Hazard in placebo arm after 4 months - prior docetaxel treatment: 8.0 % • Estimated number of events: 640

• Accrual time: 30 months

• Maximum follow-up time: 36 months

• Time of primary analysis: 46 months after study start • Uniform patient accrual

Statistical Methods:

Patients will be randomised to Alpharadin or placebo in a 2:1 ratio. Randomisation will be stratified by the following factors:

• Total-ALP < 220 U/L versus total-ALP ≥ 220 U/L • Current use of bisphosphonates: yes versus no • Any prior use of docetaxel: yes versus no

The primary efficacy endpoint, overall survival, and the secondary efficacy time-to-event endpoints (time to first disease event, time to progression in PSA and time to progression of total ALP) will be analysed using a stratified log-rank test. Further exploratory analyses of the time-to-event endpoints will be performed using a stratified proportional hazards model adjusting for other potential prognostic factors recorded at baseline. The other secondary efficacy endpoints (incidences of PSA and total-ALP responses) will be analysed using a Cochran-Mantel-Haenszel (CMH) test, stratified by each of the three stratification factors. The safety and clinical benefit endpoints will be summarised only.

Analysis Populations

The following three populations will be defined:

Intent-to-treat (ITT): All randomised patients. The ITT population will be the primary population for the analysis of the primary efficacy endpoint and for the analysis of all secondary efficacy and clinical benefit endpoints. Patients will be included in all ITT analyses according to the treatment to which they were randomised.

Safety: All randomized patients who have received at least one study drug administration. This safety population will be used in the analyses of all safety endpoints. Patients will be included in the analyses according to the treatment they received

Per-protocol (PP): All patients in the ITT population who received at least 3 study drug administrations, and did not have any major protocol violations. This population will be the secondary population for the analysis of the primary efficacy endpoint.

Data from Alpharadin treatment of placebo patients following unblinding of the study will be analysed separately.

Interim Analyses

An interim efficacy analysis will be performed during the study to provide the IDMC with an opportunity to review accumulating survival data, and stop the study early if there is evidence of overwhelming benefit. A group-sequential stopping boundary (O’Brien-Fleming) will be used to preserve the Type I error rate for the final analysis at approximately 5%.

(10)

To provide the IDMC members with supporting data as basis for their recommendation following the interim analysis, it has been specified that the IDMC may request the analysis results for the main secondary endpoints. If the study is stopped based on the recommendation of the IDMC, then all planned analyses will be performed according to what is described for the final analysis in this protocol and the statistical analysis plan.

A blinded sample size re-estimation is also planned to be performed.

Subgroup analyses

A number of sub-group analyses of both efficacy and safety variables are planned in order to examine exposure:response relationships.

An Independent Data Monitoring Committee (IDMC) will be responsible for reviewing accumulating safety data at regular intervals throughout the study and monitoring overall study conduct. The sponsor and other trial personnel will receive its recommendations only, with no analysis results being communicated. All safety data on the database at the time of defined data cut-offs will be included in the reports. At the sponsor request, the IDMC may also evaluate results of a formal interim efficacy analysis performed after approximately 50% of required endpoint events (deaths) have been observed.

(11)

2

3 LIST OF ABBREVIATIONS

AE Adverse Events

ALP Alkaline Phosphatase

ALAT Alanine Transaminase

ANC Absolute Neutrophil Count

AR Adverse Reaction

ASAT Aspartate Transaminase

ASCO American Society of Clinical Oncology

b.w. Body Weight

CMH Cochran-Mantel-Haenszel

CFR Code of Federal Regulations

CRF Case Report Form

CT Computed Tomography

CTCAE Common Terminology Criteria for Adverse Events CTX-1 C-terminal crosslinking telopeptide of type I collagen

DCF Data Clarification Forms

DK Decay correction factor

EBRT External Beam Radiation Therapy

EC Ethics Committee

ECCO European CanCer Organisation

ECG Electro CardioGraphy

ECOG PS Eastern Cooperative Oncology Group Performance Status EDTMP-Sm ethylene diamine tetra methylene phosphonate - samarium

EOD Extent of Disease

EQ-5D Euro Quality of Life

FACT-P Functional Assessment of Cancer Therapy -Prostate

FDA Food and Drug Administration

GCP Good Clinical Practice

G-CSF Granulocyte-Colony Stimulating Factor

GMP Good Manufacturing Practice

HRPC Hormone Refractory Prostate Cancer ICH International Conference on Harmonisation ICTP Type I collagen cross-linked C teleopeptide IDMC Independent Data Monitoring Committee IRB Institutional Review Board

ITT Intention to Treat

IVRS Interactive Voice Response System

kBq kilo Becquerel

LET Linear Energy Transfer

LHRH Luteinising Hormone-Releasing Hormone

LH Luteinising Hormone

MedDRA Medical Dictionary for Regulatory Authorities

MRI Magnetic Resonance Imaging

NYHA New York Heart Association

OS Overall Survival

PINP Procollagen Type I N propeptide

PP Per Protocol

PS Performance Status

PSA Prostate Specific Antigen

QoL Quality of Life

QALY Quality Adjusted Life Years

SAE Serious Adverse Event

SAP Statistical Analysis Plan

SAR Serious Adverse Reaction

SD Standard Deviation

SDV Source Data Verification

(15)

SRE Skeletal Related Events

SUSAR Suspected Unexpected Serious Adverse Reaction

TAB Total Androgen Blockade

TEAE Treatment Emergency Adverse Event

ULN Upper Limit of Normal

(16)

4 INTRODUCTION

4.1 Bone Metastases in Hormone-Refractory Prostate Cancer

Prostate cancer is the most common cancer in men worldwide and one of the leading causes of cancer-related morbidity and death.

Prostate cancer cell growth is stimulated by male hormones (androgens), in particular testosterone and its metabolite dihydro-testosterone. Therefore, patients may be treated by androgen deprivation to reduce levels of male hormones available to cancer cells. Androgen deprivation can be achieved surgically by bilateral orchiectomy (castration), or medically using LHRH-receptor agonists referred to as hormone therapy. Anti-androgens are drugs that act as androgen-receptor antagonists (e.g. flutamide, bicalutamide, ciproterone). They are frequently used concomitantly with or immediately before hormone therapy to avoid tumour flare syndrome due to an increase in LH levels secondary to LHRH treatment initiation, referred to as total androgen blockade (TAB). Unfortunately, patients ultimately stop responding to hormone therapy after being on treatment for a variable period of time and are then referred to as having hormone-refractory or androgen-independent prostate cancer. However those undergoing TAB at the time of progression may still have short-term responses to anti-androgen withdrawal. Patients continue on LHRH treatment even if they are hormone-refractory, but may stop the use of anti-androgen.

The most common site of cancer spread in men with hormone refractory prostate cancer (HRPC) is bone. Development of bone metastases is a major problem in prostate cancer and is a serious threat to a patient’s survival and quality of life. Untreated patients face severe morbidity, including bone pain, bone fracture, compression of the spinal cord and haematological consequences of bone marrow involvement. If treated successfully, these symptoms may be palliated and patients may also gain a survival benefit.

Skeletal homeostasis is carried out by continuous destruction and rebuilding of skeletal tissue. Following haematological dissemination, metastatic bone disease develops as a result of interaction between tumour cells and bone cells causing elevated bone metabolism in the tumour zones. This process bears several similarities to the events that occur in inflammation. Inflammation can be initiated by tissue damage i.e. trauma or metastatic involvement, which in turn increases osteoid turnover. Scintigraphic bone assessment relies on this turnover and is a highly sensitive technique although not specific in distinguishing between malignant diseases, inflammatory causes or fractures. The increased osteoclast and osteoblast activity in bone metastases provides a rational target for drug development 1. Unfortunately, therapeutic options at this stage of illness are very limited. Four drugs have been approved for the treatment of HRPC in Europe and the US: estramustine, mitoxantrone, zoledronic acid and docetaxel. Two large randomised trials compared docetaxel with mitoxantrone. Docetaxel was reported as showing a median survival of 18.9 months in the prednisone/docetaxel group versus 16.5 months in the prednisone/mitoxantrone group2 in the Tax 327 trial. Similarly, the SWOG 9916 study showed a median survival of 17.5 months in the docetaxel/estramustine group versus 15.6 months in the prednisone/mitoxantrone group3, leading to docetaxel FDA approval as

(17)

first-line therapy in HRPC in the US and Europe. The other chemotherapy agents (such as mitoxantrone or cyclophosphamide) and hormones can induce responses, but survival advantages are yet to be demonstrated4. Therefore, there is a lack of effective therapy after docetaxel progression in HRPC and no standard therapy is currently available. In addition to those patients who have already received docetaxel, some patients do not tolerate docetaxel, some are unwilling to receive docetaxel and some are not considered suitable for docetaxel.

Zoledronic acid, a bisphosphonate, has been shown to delay skeletal related events by inhibiting osteoclast mediated bone resorption in this population. However these results may not apply to other bisphosphonates as for example pamidronate results were not positive in the same setting.

Bone-seeking radionuclides have been developed for palliation of bone pain from metastases: Metastron (strontium-89) and Quadramet (samarium-153 EDTMP) have been approved in several countries. The bone-seeking nature of these agents results in direct delivery of beta radiation to the sites of disease. Due to the long range of the beta particles from these radioisotopes, the major dose-limiting factor with this treatment modality is toxicity to the bone marrow cells. Bone marrow toxicity limits doses of beta emitting bone-seeking radiopharmaceutical to pain palliation only. This toxicity has seriously limited their more extensive utilisation in the clinical setting.

4.2 Alpha Emitting Bone Seeking Radionuclide Radium-223

Alpharadin Injection (radium-223) is a novel alpha emitting pharmaceutical (alpha-pharmaceutical), developed by Algeta ASA. The product is based on the alpha-particle emitting radionuclide radium-223, and has shown promising properties for patients with bone metastases. The bone targeting property of radium-223 is similar to that of other earth alkaline elements, like strontium-89. However, the radiation characteristics of an alpha-particle emitting radionuclide seem to be more advantageous than a beta-emitting radionuclide. Radium-223, with a physical half-life of 11.4 days, emits high linear energy transfer (LET) alpha radiation, with a range limited to less than 100 micrometers, and can thus be used to generate very localised radiation zones. An alpha-emitting radiation source located in a target tissue, such as skeletal metastases, will deliver the radiation to a more localised volume than beta emitters, thereby reducing exposure of surrounding normal tissues.

Biodistribution studies have shown that radium-223 is selectively concentrated in bone compared to soft tissues, and that radium-223 and its progeny are retained in the bone matrix 5,6. Due to increased bone metabolism in skeletal metastases, preferential uptake in these lesions compared to normal bone is observed. As some gamma emission is associated with the decay of radium-223 and daughters, it was possible to obtain gamma camera scintigrams from some of the patients in a Phase I study with radium-223. These scintigrams confirmed a preferential uptake of radium-223 in the metastatic regions.

A significant radium-223 anti-tumour effect has been demonstrated in an experimental skeletal metastases model in nude rats intraventricularly inoculated with human breast cancer cells. All of the tumour-bearing control animals had to be sacrificed because of induced paralysis 20-30 days after tumour cell injection, whereas rats treated with >100 kBq/kg b.w. showed a significantly increased symptom free survival (p<0.05).

(18)

Approximately 40% of the rats treated with 100 kBq/kg Alpharadin were alive beyond the 67-day follow-up period compared to none in the control animals5.

Based on the encouraging results from preclinical testing, Alpharadin was brought into clinical development in August 2001. A Phase I clinical study in patients with skeletal metastases from breast and prostate cancer, was started to evaluate whether the product could be administered safely at therapeutically relevant doses. A total of 31 patients were enrolled. Twenty-five patients received a single intravenous injection in the dose escalating part of the study, with five patients at each dose level at 46, 93, 163, 213 and 250 kBq/kg b.w. Alpharadin. The patients were dosed as planned, and followed for a period of 8 weeks. Two of the prostate cancer patients were given a second injection 10 to 11 months after the first dose. Six additional prostate cancer patients were enrolled and they received repeated dosing of either 50 kBq/kg b.w. times five with three week intervals, or 125 kBq/kg b.w. times two with six week intervals. Patients were followed for 8 weeks after the last injection. In the first group one patient received four of the planned five injections, and in the second group two of the three patients received only one of the planned two injections, due to deteriorating medical condition. Modest and reversible haematological toxicity was observed, more pronounced in the higher dose groups. Dose limiting haematotoxicity was not observed. No additional myelosuppression was observed upon multiple dosing. No clinically significant trends in serum chemistry parameters were observed during the 8-week period. Transient diarrhoea (Common Terminology Criteria for Adverse Events (CTCAE) grade 1 to 2), responding well to medication, was reported by some patients in all dose groups, and was the most frequent adverse event. Nausea, vomiting and fatigue were reported more frequently by patients in the higher dose groups.

Alpharadin continued its clinical development with a Phase II program. Patient recruitment has been completed for BC1-02 Phase II study, and the study has been published7 and poster presented at the ASCO 2007 and ECCO 2007 meetings. Sixty-four HRPC patients with painful bone metastases were randomised to receive, after palliative external radiotherapy, either Alpharadin or placebo (saline) in a blinded design. The patients received multiple dosing of either 50 kBq/kg b.w. Alpharadin or saline four times at four week intervals. All patients were followed for one year without breaking the blinding code. There were no treatment discontinuations due to haematotoxicity, or no evidence of cumulative toxicity with repeated treatment with Alpharadin. Alpharadin treatment was associated with a transient decrease in mean neutrophils count compared with placebo after injection. Only CTCAE grade 1 platelet toxicity was observed and only one patient experienced CTCAE grade 3 neutrophil count toxicity in the treatment period. Alpharadin treatment was not associated with more nausea/vomiting than placebo, with constipation being the only toxicity more frequently reported in the Alpharadin treatment arm. Globally, the safety profile to date has been consistent with the Phase I data. Within the limitations of the data set, Algeta has not observed any signals of late toxicity from Alpharadin.

In terms of efficacy the BC1-02 Phase II results showed a significant improvement in serum bone markers i.e. bone-ALP (the study primary efficacy endpoint), and perhaps more importantly a delayed time to PSA progression. Median overall survival at 2 years was 65.3 weeks for Alpharadin and 46.3 weeks for placebo (hazard ratio of 2.1; p value=0.017 based on an ITT population and adjusting for baseline covariates).

(19)

The results obtained with the biochemical markers for bone-turnover (bone-ALP, CTX-I, ICTP, PINP) and tumour load (PSA) support the presence of a treatment effect during the treatment period and for one to two months after the end of treatment. These data suggest that increasing treatment duration to six months may further delay disease progression. A beneficial trend in the survival data supported a treatment effect, although survival data in 64 patients should be interpreted with caution. This will be investigated in the current Phase III program.

4.3 Benefits and Risks

Intravenous injection of radium-223 is an experimental treatment for patients with bone metastases.

Anticipated benefits of the treatment include the following: - Prolongation of overall survival

- Delay of skeletal related events

- Improvement in QoL

- Anti-tumour efficacy as measured by PSA - Palliation of bone pain

Anticipated risks attributed to Alpharadin:

- Adverse events: gastrointestinal (constipation, transient diarrhoea, nausea and vomiting) and temporary increase in bone pain a few days after injection (flare pain)

- Transient reduction in neutrophil count. Mild to moderate reversible myelosuppression may occur

- Alpharadin is a radioactive drug, and may, in the longer term, induce other primary cancers and bone marrow changes. From the data derived so far up to 2 years, there are no reports of long term toxicity

The risk profile attributed to Alpharadin is favourable compared with available products in HRPC. As for all radiopharmaceutical agents, written instructions concerning safety precautions must be given to the patients before administration and to the hospital staff before handling of radioactive products. Haematological parameters should be closely followed as a safety measure.

4.4 Rationale and Dose Selection

Prostate cancer is the most common cancer in men worldwide and one of the leading causes of cancer-related morbidity and death. HRPC has poor prognosis with a median survival of only around 1-2 years. Even though a few approved treatments are available, these have not changed the overall prognosis to any large extent. In addition, most approved cytotoxic treatments are associated with substantial side effects. Alpharadin has shown substantial clinical benefit in HRPC patients with skeletal metastases in Phase II, including statistically significant effects on PSA, markers of bone metastases metabolism, and overall survival. The Phase II data also showed that Alpharadinhad a benign adverse event profile. The present study will be initiated to further provide confirmatory data for the clinical potential of Alpharadin.

The proposed dosing regimen for the Phase III trial is 50 kBq/kg b.w. every four weeks for a 6-month treatment period (6 injections). In the completed Phase I safety, tolerability and

(20)

pharmacokinetic clinical study (ATI-BC-1), prostate or breast carcinoma patients with skeletal metastases were administered Alpharadin in single doses of 46, 93, 163, 213 or 250 kBq/kg b.w. (25 subjects) or multiple doses of five administrations of 50 kBq/kg b.w. at three week intervals (3 subjects) or two administrations of 125 kBq/kg b.w. at six week intervals (3 subjects). In the completed Phase II study, 64 hormone-refractory prostate cancer patients with painful skeletal metastases referred for external radiotherapy, received four injections of 50 kBq/kg b.w. Alpharadin (33 subjects) or placebo (31 subjects) at four weeks intervals, to examine the effects of Alpharadin on biomarkers of disease progression, skeletal related events, pain palliation, survival and safety parameters.

The efficacy and safety data from Phase II support the selection of a dosing regimen of multiple doses of 50 kBq/kg b.w. of Alpharadin given at four weeks intervals. Clinically relevant efficacy was observed, with only minor side effects and no indication of cumulative effect on bone marrow suppression upon multiple administration of Alpharadin. Currently, no data are available to assess if similar effects could be achieved with a dose lower than 50 kBq/kg b.w. However, HRPC patients have a poor prognosis with a median survival of only 1-2 years and since no curative treatment is available it is important that the dose administered is effective and well tolerated. The highly promising phase II results for Alpharadin make it a priority to make this treatment available to larger patient populations as soon as possible. Thus, the data to support selection of individual dose is considered adequate, with only minor side effects being seen with this dose and no increase in frequency or severity of adverse events being observed upon multiple administrations. In the Phase II study BC1-02, the duration of the benefit appeared to be related to duration of treatment, consequently the treatment period is planned to be extended in Phase III to prolong the anticipated benefit to the patients. A 6-month treatment period (6 administrations) is reasonable since it is comparable to the treatment duration of other approved treatments used in this patient group. Blood samples will be assessed before dosing to ensure normal haematology. The study will be supervised by an independent data monitoring committee (IDMC).

5 STUDY OBJECTIVES

5.1 Primary Objective

To compare, in patients with symptomatic HRPC and skeletal metastases, the efficacy of best standard of care plus Alpharadin versus best standard of care plus placebo, with the primary efficacy endpoint being overall survival (OS).

5.2 Secondary Objectives

To compare, in patients with symptomatic HRPC and skeletal metastases receiving either best standard of care plus Alpharadin versus best standard of care plus placebo:

• Time to occurrence of specified disease events

• Changes and time to progression in serum PSA and total ALP concentrations

• The acute and long term safety profile

• Quality of life

(21)

5.3 Endpoints

Primary Efficacy Endpoint

Overall survival (OS): time from date of randomisation to the date of death Secondary Efficacy Endpoints

Main secondary efficacy endpoints

• Time to total-ALP progression

• Total-ALP progression is defined

i. in patients with no total-ALP decline from baseline as: ≥ 25% increase from the baseline value, at least 12 weeks from baseline

ii. in patients with an initial total-ALP decline from baseline as: ≥ 25% increase above the nadir value, which is confirmed by a second value obtained three or more weeks later.

• Total-ALP response defined as:

• Confirmed total-ALP response: ≥30% reduction of the blood level, compared to the baseline value, confirmed by a second total-ALP value approximately 4 or more weeks later.

• Time to occurrence of first skeletal related event.

• A skeletal related event is the use of external beam radiotherapy to relieve skeletal symptoms or the occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral) or the occurrence of spinal cord compression or a tumour related orthopaedic surgical intervention.

• Total-ALP normalisation

• Defined as the return of total-ALP value to within normal range at 12 weeks in 2 consecutive measurements (at least 2 weeks apart) after start of treatment in patients who have their total-ALP above ULN at baseline.

• Time to PSA progression

• PSA progression is defined

i. in patients with no PSA decline from baseline as: ≥ 25% increase from the baseline value and an increase in absolute value of ≥ 2 ng/mL, at least 12 weeks from baseline ;

ii. in patients with an initial PSA decline from baseline as: ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir value, which is confirmed by a second value obtained three or more weeks later

Other secondary efficacy endpoints

• Time to occurrence of first use of external beam radiotherapy to relieve skeletal symptoms

• Time to occurrence of first use of radio-isotopes to relieve skeletal symptoms

• Time to occurrence of first new symptomatic pathological bone fractures (vertebral and non-vertebral)

• Time to occurrence of first tumour related orthopaedic surgical intervention

(22)

• Time to occurrence of first start of any other anti-cancer treatment

• Time to occurrence of first deterioration of ECOG PS by at least two points from baseline [includes death (score of 5), by definition].

• Changes in PSA

• PSA response will be derived, defined as:

• Confirmed PSA response: ≥50% reduction of the blood level, compared to the baseline value, confirmed by a second PSA value approximately 4 or more weeks later

• The percentages of change from baseline to 12 weeks, as well as the maximum decline in PSA that occurs at any point after treatment will be reported for each patient using a waterfall plot

• Changes in total-ALP

• Total-ALP response will be derived, defined as:

• Confirmed total-ALP response: ≥50% reduction of the blood level, compared to the baseline value, confirmed by a second total-ALP value approximately 4 or more weeks later

• The percentages of change from baseline to 12 weeks, as well as the maximum decline in PSA that occurs at any point after treatment will be reported for each patient using a waterfall plot

Safety Endpoints

• Incidence and severity of adverse events and laboratory abnormalities, graded according to the National Cancer Institute – Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0

• Incidence of Serious Adverse Events (SAE)

• Incidence of treatment discontinuations due to adverse events

• Incidence of potential manifestations of late toxicity, such as new primary cancers and bone marrow changes (acute myelogenous leukaemia, myelodysplastic syndrome and aplastic anaemia)

Clinical Benefit Endpoints

• Performance status (PS) response and progression defined as:

• at least a 1-point improvement or worsening, respectively, on the ECOG scale from baseline value

• Quality of life (QoL) assessed using:

• Functional Assessment of Cancer Therapy - Prostate (FACT-P) questionnaire

• EuroQoL (EQ-5D) which will also be included in the health economics analysis

The QoL forms may be used only in those countries where the forms are translated and validated.

(23)

Health Economics

A health economic analysis of the treatment is being planned in some countries. Cost data will be collected from each hospital and utilized in an economic model. Efficacy, QoL in the form of Quality-Adjusted Life-Years (QALYs), life-years gained and other data collected in this study may be used as inputs to the model.

6 STUDY DESIGN

6.1 Study Design

This is a double-blind, randomised, multiple dose, placebo-controlled, international Phase III pivotal efficacy and safety study of Alpharadin.

Patients will participate in two study periods:

• Treatment period: from first injection of Alpharadin or placebo, to 4 weeks after last injection of Alpharadin or placebo, normally 24 weeks. The study treatment consists of 6 intravenous administrations of Alpharadin or placebo (normal saline) each separated by an interval of 4 weeks. Prior to each study treatment, samples will be assessed to ensure an adequate haematology profile. Other treatments for prostate cancer should be used in accordance with routine clinical practice, at the discretion of the Investigator. If cytotoxic chemotherapy, other systemic radioisotopes or hemibody external radiotherapy treatments are considered as the best standard of care to be given during the treatment period, further study drug administrations must be discontinued

• Follow-up period: from 4 weeks after last administration of study drug until 3 years from first administration. Patients will be evaluated every 2 months until 1 year after first administration, and thereafter every 4 months until 3 years from first administration. Date of death will be collected for all patients until the last patient has been followed for 3 years. Patient management will be in accordance with routine clinical practice, at the discretion of the Investigator.

At the time of issuance protocol version 6, the interim analysis described in the Protocol Section 12 has been performed, and the Independent Data Monitoring Committee (IDMC) has confirmed that the results met the pre-defined criteria and recommended to conclude and unblind the study. The sponsor has decided to follow the recommendation from the IDMC.

On this basis, the study will be unblinded and the investigators informed about the treatment allocation for their patients. Investigators will be allowed to offer placebo patients who are still participating in the study (i.e. have not withdrawn from the study) and who fulfil the eligibility criteria as defined in this protocol addendum, a full course of Alpharadin treatment (50 kBq/kg body weight (b.w.) administered 6 times, at intervals of 4 weeks). The placebo patients entering into a new treatment period with Alpharadin will be followed up as described in the protocol and this protocol addendum, until the last patient of the original patient population has been followed up for 3 years.

A separate protocol addendum describes the study procedures for the placebo patients who are offered Alpharadin treatment: Access to Alpharadin for placebo patients in the ALSYMPCA trial (BC1-06), Version 1.0

(24)

This protocol addendum will be open for inclusion of patients until end of 2012.

There are no changes to the treatment and follow-up of the patients who have already received Alpharadin before unblinding of the study or of the patients who have received placebo before unblinding but who do not enter into treatment with Alpharadin. These patients will continue follow up as previously planned in the protocol.

Data from Alpharadin treatment of placebo patients following unblinding of the study will be analysed separately, as described in the protocol addendum.

(25)

6.2 Study Flow Chart

TREATMENT PERIOD Placebo (isotonic saline) + Best standard of care

6 IV administrations separated by 4 weeks intervals

RANDOMISATION

2:1 (Alpharadin:placebo) Stratification:

• Total ALP < 220 U/L versus total-ALP ≥ 220 U/L • Current use of bisphosphonates: yes versus no • Any prior use of docetaxel: yes versus no

TREATMENT PERIOD Alpharadin (50 kBq/kg b.w.)

+ Best standard of care

6 IV administrations separated by 4 weeks intervals

FOLLOW-UP PERIOD

4 weeks after last study drug administration until 3 years from first study drug administration.

Patients will be evaluated every 2 months for 6 months, and then every 4 months to 3 years

Informed consent SCREENING

Patient fulfills eligibility criteria Patient inclusion

(26)

7 SELECTION OF STUDY POPULATION

The target population is patients with progressive symptomatic HRPC, with at least two skeletal metastases on bone scan and no known visceral metastases.

Specifically the target population is

• Patients who have received docetaxel

• Patients who are not fit enough to receive docetaxel

• Patients not willing to receive docetaxel,

• Patients for whom docetaxel is not available for other reasons .

“Symptomatic” is defined as either regular (not occasional) use of analgesic medication for cancer related bone pain (≥ level 1; WHO ladder for cancer pain), or treatment with EBRT for bone pain (the EBRT should be within previous 12 weeks before randomisation).

“Best standard of care” is regarded as the routine standard of care at each centre, for example local external beam radiotherapy, corticosteroids, antiandrogens, oestrogens (e.g. stilboestrol), estramustine or ketoconazole.

The screening haematology values are recommended to be measured at a maximum of 1 week prior to randomisation and the first injection should be done as soon as possible after randomisation.

PSA progression has to be documented by 2 consecutive rises in PSA over a previous reference value within 6 months prior to randomisation (thus, reference value < progression value 1 < progression value 2). The progression values should be at least one week apart. It is accepted that after the documented PSA progression, the PSA could decline prior to randomisation, provided that the screening value is at least 5ng/ml.

7.1 Eligibility Criteria

Inclusion criteria:

1. Histologically or cytologicallyconfirmedadenocarcinoma of the prostate 2. Known hormone refractory disease defined as:

• Castrate serum testosterone level: ≤ 50 ng/dL (1.7 nmol/L)

• Bilateral orchiectomy or maintenance on androgen ablation therapy with LHRH agonist or polyestradiol phosphate throughout the study

• Serum PSA progression defined as two consecutive increases in PSA over a previous reference value, each measurement at least 1 week apart

3. Serum PSA value ≥ 5 ng/mL (µg/L)

4. Multiple skeletal metastases (≥ 2 hot spots) on bone scintigraphy within previous 12 weeks

5. No intention to use cytotoxic chemotherapy within the next 6 months

6. Either regular (not occasional) analgesic medication use for cancer related bone pain or treatment with EBRT for bone pain within previous 12 weeks

7. Age ≥ 18 years

(27)

9. Life expectancy ≥ 6 months 10. Laboratory requirements:

a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L b. Platelet count ≥ 100 x109/L

c. Hemoglobin ≥ 10.0 g/dL (100 g/L; 6.2 mmol/L)

d. Total bilirubin level ≤ 1.5 institutional upper limit of normal (ULN) e. ASAT and ALAT ≤ 2.5 ULN

f. Creatinine ≤ 1.5 ULN g. Albumin >25 g/L

11. Willing and able to comply with the protocol, including follow-up visits and examinations

12. Must be fully informed about the study and has signed the informed consent form Exclusion criteria

1. Treatment with an investigational drug within previous 4 weeks, or planned during the treatment period

2. Eligible for first course of docetaxel, i.e. patients who are fit enough, willing and where docetaxel is available

3 Treatment with cytotoxic chemotherapy within previous 4 weeks, or planned during the treatment period, or failure to recover from adverse events due to cytotoxic chemotherapy administered more than 4 weeks ago (however ongoing neuropathy is permitted

4. Prior hemibody external radiotherapy

5. Systemic radiotherapy with strontium-89, samarium-153, rhenium-186or rhenium-188 for the treatment of bony metastases within previous 24 weeks

6. Prior treatment with radium-223

7. Blood transfusion or erythropoietin stimulating agents within previous 4 weeks 8. Other malignancy treated within the last 5 years (except non-melanoma skin cancer

or low-grade superficial bladder cancer)

9. History of visceral metastasis, or visceral metastases as assessed by abdominal/pelvic CT or chest x-ray within previous 8 weeks2 10. Malignant lymphadenopathy exceeding 3 cm in short-axis diameter

11. Imminent or established spinal cord compression based on clinical findings and/or MRI

12. Any other serious illness or medical condition such as, but not limited to:

• any uncontrolled infection

• cardiac failure NYHA III or IV

• Crohn’s disease or Ulcerative colitis

• Bone marrow dysplasia

13. Unmanageable faecal incontinence

2

Abdominal/pelvic MRI will be accepted in place of abdominal/pelvic CT. CT covering the chest area will be accepted in place of chest x-ray.

(28)

7.2 Dose Adjustment and Delay, Treatment Discontinuation,

Withdrawal and Study Completion Criteria

The patient may discontinue treatment, but still continue in the study for the follow-up assessments. Every effort must be made to get follow up and survival data for each patient. When a patient is withdrawn from the study, i.e. is not attending any follow-up visits, the study withdrawal/completion page in the Case Report Form (CRF) is to be filled in. However, survival data will be collected after withdrawal from the study, provided that the patient agrees to collection of data after withdrawal. Single patient termination is per definition when the patient is withdrawn or when the patient has died or completed his 3 years follow-up visit.

7.2.1 Dose Adjustments

Every effort will be made to administer the full dosing regimen. Single dose level adjustment is not permitted.

7.2.2 Dose Delay and Treatment Discontinuation

Study visits during the treatment period should occur at 4 weeks intervals (within a window of -3 days to +7 days). The same visit interval (4 weeks) applies between all treatments. If the window of -3 days to +7 days cannot be met, contact your CRA for advice. A study drug administration may be delayed by no more than four weeks for recovery of adverse events. In case of a treatment delay greater than four weeks, treatment should be discontinued. It is important to note that in general (unless otherwise agreed), in cases where study drug has been ordered, the time window is reduced to -3 days to + 3 days, due to decay. If administration has to be postponed more than 3 days after drug has been ordered, replacement of the drug order is required.

When patients discontinue treatment they will have a discontinuation assessment 4 weeks after the last injection. They will then enter the follow-up phase where they will be evaluated every 2 months until 1 year after the 1st study drug administration, and thereafter every 4 months until death or until 3 years from treatment initiation. Date of death will be collected for all patients until the last patient has been followed for 3 years.

7.2.2.1 Dose Delay and Treatment Discontinuation due to Adverse Events Disease progression:

In this patient population, disease progression is expected. Bone pain is a prominent symptom; other symptoms may include fatigue, nausea, anorexia, depression, constipation (also secondary to opioids), bowel and bladder symptoms, lymphoedema, neurological and haematological complication as well as metastases to other organs, such as liver and lung. The Investigator should delay cytotoxic chemotherapy, other systemic radioisotope, hemibody external radiotherapy or other investigational drug until the follow-up period. If such treatments have to be given during the treatment period, further study drug administrations must be discontinued. These medications should not be given before four weeks wash-out period after last administration of study drug, provided the patient’s bone marrow is not compromised.

(29)

Continuation in the study of a patient with disease progression will be according to the Investigator’s judgement.

Myelosuppression:

Changes in haematology parameters may occur after injection of study drug.

If a patient experiences CTCAE grade 3-4 neutropenia or thrombocytopenia lasting > 14 days, further study drug administrations must be discontinued.

If a patient experiences CTCAE grade 3-4 neutropenia the study drug administration should be delayed until recovery to grade 2 (minimum 1.0 x 109 /L) or better.

In case of thrombocytopenia grade 3-4 the study drug administration should be delayed until recovery to CTCAE grade 2 (minimum 50 x 109 /L) or better.

In case of haemoglobin CTCAE grade 3-4, the value needs to recover to CTCAE grade 2 (minimum 8.0 g/dL) or better before next study drug administration. Blood transfusion is acceptable between study drug administrations.

Gastrointestinal events: Diarrhoea:

No prophylactic treatment for diarrhoea is recommended. Antidiarrhoeals can be used when needed. A further dose of study medication should not be given before recovered to CTCAE grade 2 or baseline.

Nausea/Vomiting:

No prophylactic treatments for nausea or vomiting are recommended, but anti-emetic drugs can be used when needed. A further dose of study medication should not be given before recovered to CTCAE grade 2 or baseline.

Constipation:

Patients can continue laxative as concomitant medication, but start of prophylactic treatments before study drug injection are not recommended. Laxative can be used when needed. A further dose of study medication should not be given before recovered to CTCAE grade 2 or baseline.

Spinal Cord Compression:

If the patient experience spinal cord compression during the treatment period, the patient should be treated for the event, and may receive further study drug administration if adequately recovered within the treatment window (not more than 4 weeks delay between the injections).

Surgical Intervention:

If surgery is required, the patient should continue with study treatment, if this is considered safe in the treating Investigator’s opinion. The surgeon needs to be notified that the patient may have been given radioactive drug, and needs to follow the guideline for radioactive protection.

(30)

Non-pathological fractures:

For traumatic fracture in weight bearing bones during treatment phase, the study drug administration should be delayed 2-4 weeks from fracture.

Pathological fractures:

These may occur from either progressive disease or increased physical activity associated with significant pain palliation. Pathologic fractures are to be treated in a manner that attempts to maintain the best functional status and quality of life. Study treatment may continue as planned.

Any Other Toxicity:

If a patient experiences any non-haematological grade CTCAE grade 4 toxicity lasting > 7 days despite adequate treatment, further study drug administrations must be discontinued.

7.2.2.2 Supportive Care Guidelines

Ancillary Treatment (guidelines):

Persistent neutropenia (Neutrophils/Granulocytes CTCAE Grade 4 (<0.5x109/L) without fever These patients may be started on Granulocyte-Colony Stimulating Factor (G-CSF) 5 µg/kg/d sc until the neutrophil count has reached the local hospitals reference range.

Neutropenia with fever (Neutrophils/Granulocytes CTCAE Grade 3-4 (<1x109/L); fever >38.50_C)

Blood cultures will be obtained and the patient started on empiric antibiotics for as long as clinically indicated. It is highly recommended that the patient receive G-CSF 5 µg/kg/d sc until the neutrophil count has reached the local hospitals reference range with two separate measurements, at least 12 hours apart.

Severe thrombocytopenia (CTCAE Grade 4 (<25.0x109/L) or bleeding with CTCAE Grade 3-4 (<50.0x109/L)

Platelets will be transfused to maintain platelet count >50 x 109/L or higher if clinically indicated to control bleeding. Epsilon aminocaproic acid may be given to patients with mucosal bleeding and platelet count CTCAE grade 3-4.

Severe anaemia (Haemoglobin CTCAE Grade 3 (<80x109g/L; 8.0 g/dL; 4.9 mmol/L))

Patients will be transfused with packed red cells to maintain haemoglobin value >80 g/L; 8.0 g/dL; 4.9 mmol/L.

7.2.3 Withdrawal

In accordance with the Declaration of Helsinki, each patient is free to withdraw from the study at any time. Investigator(s) also have the right to withdraw patients from the study in the event of illness, adverse events (AEs), or other reasons concerning the health or well being of the patient, or in the case of lack of cooperation.

Should a patient decide to withdraw after administration of the investigational product(s), or should the Investigator(s) decide to withdraw the patient, all efforts will be made to complete and report the observations as thoroughly as possible. A complete final evaluation at the time of the patient’s withdrawal should be made and an explanation given of why the patient is withdrawing or being withdrawn from the study.

Supplement: ALSYMPCA (BC1-06) Study Protocol and Statistical Analysis Plan

1

PROTOCOL SYNOPSIS

2

TABLE OF CONTENTS

3

LIST OF ABBREVIATIONS

4

INTRODUCTION

4.1

Bone Metastases in Hormone-Refractory Prostate Cancer

4.2

Alpha Emitting Bone Seeking Radionuclide Radium-223

4.3

Benefits and Risks

4.4

Rationale and Dose Selection

5

STUDY OBJECTIVES

5.1

Primary Objective

5.2

Secondary Objectives

5.3

Endpoints

6

STUDY DESIGN

6.1

Study Design

6.2

Study Flow Chart

7

SELECTION OF STUDY POPULATION

7.1

Eligibility Criteria

7.2

Dose Adjustment and Delay, Treatment Discontinuation,

Withdrawal and Study Completion Criteria