Upload
shanon-summers
View
222
Download
1
Embed Size (px)
Citation preview
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Radiotherapy from within The Bone For Patients with Metastatic
Castration-Resistant Prostate Cancer (mCRPC)
Tony Wu.
Department of Surgery, Kaohsiung Veterans General Hospital
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Goals of treatment for mCRPC
Improve overall survivalDelay symptomsMaintain quality of life
Frequency and Impact of Skeletal Involvement among Patients with Advanced Cancer
Cancer Type Frequency 5-yr Survival Median SurvivalMyeloma 95%–100% 10% 20 months
Breast 65%–75% 20% 24 months
Prostate 65%–75% 25% 40 months
Lung 30%–40% 2% to < 5% < 6 months
Renal 20%–25%
Bladder 40%
Melanoma 14%–45%
Thyroid 60%
Frequency adapted with permission from Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(suppl): 1588-1594.Copyright © 2000 American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.1. Mundy GR. Mechanisms of bone metastasis. Cancer. 1997;80:1546-1556. 2. Coleman RE. Skeletal complications of malignancy. Cancer.1997;80:1588-1594. 3. Ginsberg RJ, Vokes EE, Rosenzweig K. Non-small cell lung cancer. In: DeVita VT, Jr Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Philadelphia: Lippincott Williams & Wilkins; 6th ed. 2001:925-983.
3
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Zoledronic acid, denusumab, radium 223
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Strontium 89 acts as a calcium mimic targets bone metastases
Ca
Sr
Ba
Ra
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
First use of strontium-89
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Strontium revisited
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Slide 8
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Slide 13
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Slide 14
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Radium-223Radium-223 acts
as a calcium mimic
Naturally targets new bone growth in and around bone metastases
Radium-223 is excreted by the small intestine
Ca
Sr
Ba
Ra
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Phase I biodistribution study of Radium-223
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Radium-223 Dichloride Solution for Injection
◦ Radium-223 is predominantly an α-emitter
◦ t½ = 11.43 days ◦ Of the total decay energy
95.3% emitted as particles 3.6% emitted as particles 1.1% emitted as γ or X-rays
◦ Easily measured on standard instruments (dose calibrators / survey meters)
Radium-223 decay chain1
1. Henriksen et al. Cancer Res 2002;62:3120–5.
b-
1.37 MeV
211Po516 ms
223Ra11.43 d
219Rn3.96 s
215Po1.78 ms
211Pb36.1 m
207Tl4.77 m
211Bi2.17 m
207Pbstable
a5.78 MeV
a6.88 MeV
a7.53 MeV
a6.68 MeV
a6.68 MeV
(99.73%)
(0.27%)
b-
584keV
b-
1.42 keV
Page 20 • Radium-223 Dichloride - Site Training V1.1 • Covance
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Why Alpha?
◦ a-particles have a high energy, but short path length - which minimizes damage to healthy tissue surrounding the cancer cells
◦ In contrast, ß-particles - used in bone pain palliation agents produce low-energy radiation and a longer track length
α β
Relative particle mass 7000 1
Initial energy (MeV) 3–8 0.01–2.5
Range in tissue (μm) 40–90 50–5000
LET (KeV/μm) 60–230 0.015–0.4
Charge +2 –1
Ion pairs/μm 2000–7000 5–20
DNA hits to kill cell 1–5 100–1000
Relative biological effectiveness
20 1
The properties of a-emitters allow: Localised cell killing - high
radiation dose in a smaller area Irradiation of a smaller area
and better targeting Minimal non-target toxicity
(e.g. bone marrow)
Page 21 • Radium-223 Dichloride - Site Training V1.1 • Covance
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Slide 25
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Bq V.S Ci
Antoine Henri BecquerelThe Nobel Prize in Physics 1903
• The becquerel (symbol Bq) (pronounced: 'be-kə-rel) is the SI derived unit of radioactivity.
• 1 Bq is defined as the activity of a quantity of radioactive material in which one nucleus decays per second.
• The becquerel succeeded the curie (Ci),
an older, non-SI unit of radioactivity based on the activity of 1 gram of radium-226.
1 Ci = 3.7×1010 Bq = 37 GBq
1 μCi = 37,000 Bq = 37 kBq
1 Bq = 2.7×10−11 Ci = 2.7×10−5 µCi
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA Study EndpointsPrimary Endpoint
◦Overall survival (OS)Secondary Endpoints
◦Time to first SRE◦Time to total ALP progression◦Total ALP response◦Total ALP normalization◦Time to PSA progression◦Safety◦Quality of life
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA OS Analyses
Planned interim analysis (IA)◦ 314 events from 809 patients randomized at the time of the IA;
Cut-off October 2010◦ June 3, 2011 the Independent Data Monitoring Committee (IDMC)
recommended stopping the trial early due to evidence of a significant treatment benefit
Updated analysis◦ 528 events from all 921 patients randomized to the study
◦ Updated analysis conducted prior to placebo patients crossing over to Radium-223 and when Radium-223 patients had completed treatment; Cut-off July 2011
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA Overall Survival
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA Time to First Skeletal-Related Event
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA OS Analyses
Planned interim analysis (IA)◦ 314 events from 809 patients randomized at the time of the IA;
Cut-off October 2010◦ June 3, 2011 the Independent Data Monitoring Committee (IDMC)
recommended stopping the trial early due to evidence of a significant treatment benefit
Updated analysis◦ 528 events from all 921 patients randomized to the study
◦ Updated analysis conducted prior to placebo patients crossing over to Radium-223 and when Radium-223 patients had completed treatment; Cut-off July 2011
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA Updated AnalysisPatient Demographics and Baseline Characteristics (ITT N = 921)
ParameterRadium-223
n = 614Placebon = 307
Age, y Mean 70.2 70.8
Race, n (%) Caucasian 575 (94) 290 (95)
Baseline ECOG score, n (%) ≤ 1 2
536 (87)76 (12)
265 (86)40 (13)
Extent of disease, n (%) < 6 metastases 6–20 metastases > 20 metastases/superscan
100 (16)262 (43)249 (41)
38 (12)147 (48)121 (40)
WHO ladder, cancer pain index ≥ 2, n (%) 345 (56) 168 (55)
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA Updated AnalysisPatient Baseline Characteristics (ITT N = 921)
ParameterMedian (min, max)
Radium-223(n = 614)
Placebo(n = 307)
Haemoglobin, g/dL 12.2 (8.5-15.7) 12.1 (8.5-16.4)
Albumin, g/L 40 (24-53) 40 (23-50)
Total ALP, µg/L 211 (32-6431) 223 (29-4805)
LDH, U/L 315 (76-2171) 336 (132-3856)
PSA, µg/L 146 (3.8-6026) 173 (1.5-14500)
Current bisphosphonates Yes, n (%) 250 (40.7) 124 (40.4)
Prior docetaxel Yes, n (%) 352 (57.3) 174 (56.7)
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA Updated AnalysisPatient Disposition
Radium-223N = 614
PlaceboN = 307
Patients treated, n 599 302
Median number of injections, range
6 (1-6) 5 (1-6)
Received all 6 injections, n (%) 387 (63) 145 (47)
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA Updated Analysis: Radium-223 Improved OS Across All Patient Subgroups
SUBGROUP
PATIENTS (n) MEDIAN OS (months)
HR 95% CIRADIUM-
223 PLACEBORADIUM-
223 PLACEBO
All patients 614 307 14.9 11.3 0.70 0.58-0.83
Total ALP<220 U/L 348 169 17.0 15.8 0.82 0.64-1.07
≥220 U/L 266 138 11.4 8.1 0.62 0.49-0.79Current use of bisphosphonates
Yes 250 124 15.3 11.5 0.70 0.52-0.93
No 364 183 14.5 11.0 0.74 0.59-0.92
Prior use of docetaxelYes 352 174 14.4 11.3 0.71 0.56-0.89
No 262 133 16.1 11.5 0.74 0.56-0.99
Baseline ECOG PS0 or 1 536 265 15.4 11.9 0.68 0.56-0.82
≥2 77 41 10.0 8.4 0.82 0.50-1.35
Extent of disease<6 Metastases 100 38 27.0 NE 0.95 0.46-1.95
6-20 Metastases 262 147 13.7 11.6 0.71 0.54-0.92
>20 Metastases 195 91 12.5 9.1 0.64 0.47-0.88
Superscan 54 30 11.3 7.1 0.71 0.40-1.27
Opioid useYesa 345 168 13.9 10.4 0.68 0.54-0.86
Nob 269 139 16.4 12.8 0.70 0.52-0.93FavorsRadium-223
FavorsPlacebo
ALP, alkaline phosphatase; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio.a. Includes patients with a score of 2 or 3 on the World Health Organization (WHO) ladder for cancer pain. b.Includes patients without pain or opioid use at baseline and patients with a score of 1 on the WHO ladder for cancer pain.SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213-23.
0.5 2.01.0
37
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
39
SSE (ALSYMPCA) SRE
Symptomatic Skeletal Event Skeletal Related Event
Definition Spinal cord compression Spinal cord compression
Tumor-related orthopedic Surgical intervention
Surgery to bone
New symptomatic pathological fractures
Pathological fractures
Use of EBRT to relieve skeletal symptoms
Radiation therapy to bone
Hypercalcemia of malignancy
Characteristics No regular radiologic image and more clinical relevant
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Time to 1st Symptomatic Skeletal Event, By Baseline Stratification Factors
5.7 mon
2.5 mon
6 mon 6.2 mon
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Time to 1st Symptomatic Skeletal Event, By Baseline Stratification Factors
9.4 mon
3.4 mon
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Relative Risk Of Individual Symptomatic Skeletal Event components
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ZA delayed first SRE in bone metastatic CRPC
Every 3~4 weeks
Adapted from Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.
(16.3 mons)
(10.7 mons)
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Denosumab vs. ZA: time to first on-study SRE
Fizazi K, et al. Lancet. 2011;377:813-822.
3.6 mons
ALSYMPCA Updated AnalysisSecondary Endpoints: ALP and PSA
Radium-223n (%)
Placebon (%)
P value
Total ALP response 30% reduction 50% reduction
233 (47)135 (27)
7 (3)2 (<1)
<0.001 <0.001
Total ALP normalization*
109 (34) 2 (1) < 0.001
*In patients who had elevated total ALP at baseline.
Hazard ratio 95% CI
P value
Time to Total ALP progression
0.167 (0.129, 0.217)
<0.00001
Time to PSA progression 0.643
(0.539, 0.768) <0.00001
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Ra-223 early access program (EAP)
phase 2 prospective, interventional, open-label, multicenter study
42% had improved pain—a decrease of ≧ 2 in BPI-SF scores without worsening;
18% had stable pain or decrease of < 2 points28% had worsening pain—an increase of ≧ 2
points or initiation of opioids—and never had improvement in pain.
10% experienced both improvements and worsening of pain at different times during treatment with Ra-223.
Christopher Sweeney, 2015 ASCO
ALSYMPCA Updated AnalysisAEs of Interest
All Grades Grades 3 or 4
Patients with AEs n, (%)
Radium-223n = 600
Placebon = 301
Radium-223n = 600
Placebo n= 301
Hematologic
Anemia 187 (31) 92 (31) 77 (13) 39 (13)
Neutropenia 30 (5) 3 (1) 13 (2) 2 (1)
Thrombocytopenia 69 (12) 17 (6) 38 (6) 6 (2)
Non-Hematologic
Bone pain 300 (50) 187 (62) 125 (21) 77 (26)
Diarrhea 151 (25) 45 (15) 9 (2) 5 (2)
Nausea 213 (36) 104 (35) 10 (2) 5 (2)
Vomiting 111 (19) 41 (14) 10 (2) 7 (2)
Constipation 108 (18) 64 (21) 6 (1) 4 (1)
Safety of Cytotoxic Chemotherapy Following Rd-223 Therapy
Number of deaths and causality during 30 days post Chemo and limited available hematologic data were similar in both groups
2012 ESMO
1.5-Year Posttreatment Follow-up <br />of Radium-223 Dichloride (Radium-223) <br />in Patients With Castration-Resistant Prostate Cancer (CRPC) and <br />Bone Metastases From the <br />Phase 3 ALSYMPCA Study
Presented By Sten Nilsson at 2014 Genitourinary Cancers Symposium
ALSYMPCA Long-term Follow-Up
Presented By Sten Nilsson at 2014 Genitourinary Cancers Symposium
Conclusions
Presented By Sten Nilsson at 2014 Genitourinary Cancers Symposium
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Optimal timing of ra-223
No clear data suggesting that treatment earlier or later with radium-223 is ideal.
if ra-223 is used after failure of abiraterone or enzalutamide, fewer men complete ≧4 cycles of therapy.
Prolonged overall survival was associated with receipt of 5 to 6 versus 1 to 4 ra-223 injections,
radium-223 can be safely given concurrently with other treatments, including enzalutamide, abiraterone acetate, and even docetaxel.
Tanya Dorff. 2015 ASCOEarly use
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Optimal timing of ra-223
If used too early, patients may not experience profound reduction in pain
If used later, the treatment can have a more profound effect due to the greater disease burden in the bone.
Later use may ultimately lead to greater uptake and delivery of radium to the bone due to more areas of bone turnover and drug incorporation.
Tanya Dorff. 2015 ASCO
Late use
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALSYMPCA AP in Taiwan
◦National Taiwan University Hospital, ◦Taipei Veterans General Hospital, ◦Taipei Chang-Gung Memorial Hospital◦Kaohsiung Veterans General Hospital,
◦16 mCRPC patients
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Gleason ADT response
Time to mCRPC
Tx. after CRPC
CRPC to Ra 223
Ra 223 dose
KS03 3+4 Good 25 Tasq. 63 6
KS04 2~6 Good 67 Docet 84 5
KS05 8~10 Poor 36 AA 37 6
NTU1 4+3 Poor 19 Docet 10 6
NTU2 9 Good 8 Nil 13 4
NTU4 9 Fair 14 Docet 7 3
NTU5 8 Good 9 Carb+docet 34 6
NTU7 7 Good 23 docet 48 2
TPE4 8~10 Good 9 Docet 55 6
TPE5 8~10 Good 23 Nil 29 6
TPE7 2~6 Good 13 Nil 2 6
TPE8 8~10 Good 50 AA 40 6
CG01 8~10 Good 116 nil 7 6
CG02 8~10 Good 8 Docet 10 4
CG03 4+3 Good 108 AA 6 6
CG05 4+3 Good 22 nil 22 5
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
PSA response
58
RADIUM-223 PLACEBOP
VALUE
ALSYMPCA≥30% Reduction in PSA blood levels at week 12, %
16 6 <0.001
ALSYMPCA-AP in TW 6 - -
ALSYMPCA ≥30% Reduction in PSA blood levels sustained through end of treatment (4 weeks after last injection), %
14 4 <0.001
ALSYMPCA-AP in TW 0 - -
ALP, alkaline phosphatase; PSA, prostate-specific antigen.SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213-23.
All Taiwanese patients never have local therapyRadium 223 cannot target prostate gland
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALP / BPI ChangeWBBS C1D1 C2D1 C3D1 C4D1 C5D1 C6D1 EOT
KS03 >20 BPI 3 3 0 3 7 8 9
ALP -51 % -58 % -54% -54 % -62% -62%
KS04 6~20 BPI 9 3 5 0 5
ALP -9% +2 % -12 % -7%
KS05 6~20 BPI 1 0 3 0 0 0 0
ALP -62 % -73% -70 % -64% -55 % -48%
NTU1 >20 BPI 1 1 1 1 4 4 10
ALP -9 % -20 % -23 % +7 % -5% -25 %
NTU2 >20 BPI 9 9 9 8 9
ALP -1 % +63% +66% +244 %
NTU4 >20 BPI 4 2 1 3
ALP +32% -14% -11%
NTU5 >20 BPI 7 9 6 9 8 7 9
ALP -31 % -22 % -10 % -7% -7 % -29%
NTU7 >20 BPI 10 9 6
ALP +13 % -33 %
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALP / BPI ChangeWBBS C1D1 C2D1 C3D1 C4D1 C5D1 C6D1 EOT
TPE4 6~20 BPI 6 3 8 6 2 4 2
ALP -25 % -33% -31% -41 % -40 % -40%
TPE5 <6 BPI 4 4 4 2 5 9 7
ALP -26% -32 % -27% -42 % -38 % -39 %
TPE7 >20 BPI 5 5 6 7 4 1 5
ALP -16% -29 % -39% -53 % -71% -71 %
TPE8 <6 BPI 6 6 5 7 4 6
ALP -15 % +1 % -36 % -15 % +115 %
CG01 <6 BPI 6 5 6 5 4 5 0
ALP -6 % -18% -12 % -22 % -22 % -13 %
CG02 >20 BPI 7 6 7 8 8
ALP -35 % -50% -60 % -59 %
CG03 >20 BPI 7 7 5 7 5 5 5
ALP -6 % +2 % -6% -14 % -9% -19%
CG05 >20 BPI 5 5 4 2 0 6
ALP -43% -77% -78 % -73% -47%
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
61
SECONDARY EFFICACY ENDPOINTS
RADIUM-223
(n = 614)PLACEBO(n = 307)
HAZARD RATIO
(95% CI)P
VALUE
Median time to total ALP progression (months) 7.4 3.8 0.17 (0.13-
0.22)<0.00
1
Total ALP response (≥30% reduction), n (%)a
233/497 (47) 7/211 (3) — <0.00
1
Total ALP normalization, n (%)a,b 109/321 (34) 2/140 (1) — <0.00
1
ALSYMPCA: ALP Response and Normalization
tALP ≥ 30% tALP ≥ 50%0%
10%
20%
30%
40%
50%
60%
44%
31%
50%
20%
total (n=16)Complete treatment (n=10)
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Results ... ... ... Pain score. Most patients reported pain palliation. Pain relief, defined as a change in
pain score of >10 (26), was observed in more than half of the patient population, for all time points compared with the baseline. At the 1-week point, 52% reported improvement, 36% unchanged, and 12% worse pain. At the 4-week point, 60% reported improvement, 20% unchanged, and 20% worse pain. At the 8-week point, 56% reported improvement, 24% unchanged, and 20% worse pain. It should be noted that two of the patients had no skeletal pain at baseline and were therefore limited to the unchanged or worse pain categories. No clear dosage response relationship could be observed. A transient increase in bone pain (i.e. a “flare” response) was reported in seven (28%) of the patients during the first week after treatment.
Dose Escalating Phase I study
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Initial experience of radium-223 treatment for metastatic castrate resistant prostate cancer in community setting. 2014 ASCO Annual MeetingCitation: J Clin Oncol 32, 2014 (suppl; abstr e16106)
Background: …. Methods: Clinical data from 19 mCRPC patients treated with Ra-223 was collected from a
large multi-disciplinary group. In accordance with the FDA’s recommended dosage, Ra-223’s monthly injections were composed of 1 dose of 50 kBq/kg, for 6 months. Up to the third injection, the World Health Organization’s (WHO) ladder for cancer pain was assessed and the pain pattern evaluated and classified in groups: no or minimal pain relief, worsening and improvement of pain. Also, short-term incidence of side effects was reported together with the hematologic parameters at each injection. Data is expressed as a median (range).
Results: This cohort was composed of 19 Caucasian men aged 74 (53-85) years old, and all suffered bone metastasis. At baseline, 13.3% graded the pain at 1 according to the WHO pain score. At the first follow-up, 27 (19-35) days after the first injection, 21.5% (2/19) noticed pain relief, and 37.5% had a WHO score of 1. 22 (21-22) days after the second injection, 44.4% (8/18) had reduced pain symptoms, and 37.5% had a WHO score of 1. At the third follow-up, 35 (22-35) days after the third injection, 50% (6/12) had pain relief, and 50% had a WHO score of 1. Also, for 10.5% (n=2) of our cohort, pain symptoms worsened while 21% (n=4) reached total pain remission by the third injection. Increased bowl movement frequency was observed in 10.5% of our cohort, diarrhea in 31.6%, constipation in 5.3%, nausea in 26.3%, vomiting in 5.3%, bone pain flair response in 26.3% and lower limb edema in 10.5%.
Conclusions: Our short-term results demonstrated promising bone-pain relief effect of Ra-223 in 50% of our patients even after a maximum of only three injections. Encountered side effects were mild including mostly gastro-intestinal symptoms, but a 21.3% platelet reduction
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Adverse Events
Pain: 7(43.8%)Nausea/vomiting: 6(37.5%)Anorexia: 3 (18.8%)Hematuria: 4 (25%)AUR: 2 (12.5%)HypotensionLFT abnormal
Anemia: 4 (25%)WBC decrease: 1 (6.3%)Plt decrease: 2 (12.5%)Septic shock: 1Hypocalcemiahypokalemia
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Introduction Product name Radium-223 dichloride solution for injection
Brand (Generic) Name: Xofigo®
Chemical name Radium-223 dichloride (223RaCl2)
Primary indication: Treatment of CR/HR prostate cancer in patients with bonemetastases
Dosage form Sterile, isotonic aqueous solution of radium-223 dichloride
Mode of action Alpha irradiation / ablation of cancer cells
Dosing regimen 6 doses given at 4 week intervals via intravenous injection
Manufacturer: Institute for Energy Technology (IFE), NorwayAlgeta ASA, Norway (for release)
Development status: Approval by the US FDA in May 2013, approval in Europe in Nov 2013
Page 67 • Radium-223 Dichloride - Site Training V1.1 • Covance
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Radium-223 Dichloride Solution for Injection
◦ A standardized, stable, vial-based product that is easy to use ◦ Ready to use, direct injection via syringe
- No generators/elutions required - No kit preparation, no chelating to targeting agent
◦ Glass vial; 6 mL solution ◦ 6 MBq (162 µCi) radium-223 per vial
(at reference date)◦ Radioactivity concentration = 1000 kBq/mL
(at reference date) ◦ Detectable with standard dose calibrators/probes◦ Shelf-life: 28 days◦ No long-lived radioactive waste products after decay*
Page 68 • Radium-223 Dichloride - Site Training V1.1 • Covance
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Dose of Radium-223 Compared with Common RadiopharmaceuticalsRadiopharmaceutical Indication Dose
(MBq)
Ra-223 Dichloride Bone metastases
3.5
Tc-99m HDP Scintigraphy 740
F-18 FDG PET imaging 300
I-131 Tositumomab NHL 3108
Sm-153 EDTMP Bone pain
2590
Y-90 Ibritumomab tiuxetan
NHL 1184
In comparison, the patient dose of radium-223 dichloride is considerably lower: 3.5 MBq (95 µCi) (70 kg body weight)
Page 69 • Radium-223 Dichloride - Site Training V1.1 • Covance
Pharmacy and Administration of Radium-223
70
• Ready to use1
• Long shelf life (28 days)
• Ready to use1
• Long shelf life (28 days)
• One visit per dose• IV injection• Outpatient treatment2
• One visit per dose• IV injection• Outpatient treatment2
1. Nilsson et al. Presented at: American Society for Radiation Oncology annual meeting 2010; poster 2385. 2. Biggin. Eur J Nucl Med Mol Imag. 2007;34:S391 Abstract P646.
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
ALYSMPCA Updated Analysis ConclusionsRadium-223 compared with placebo in CRPC
patients with bone metastases:◦ Significantly prolonged median OS by 3.6 months
(HR = 0.695; P = 0.00007) 30.5% reduction in risk of death
◦ Significantly prolonged median time to first SRE by 5.5 months
(HR = 0.64; P < 0.0001)
Further follow-up in all randomized patients continues to show highly favorable safety profile
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Ra-223 showed significantly better preservation of QOL, with improved functioning and well-being, compared to Placebo
Similar safety profiles were observed in patients who received chemo after Ra-223 and in those who received chemo after placebo
ALYSMPCA Updated Analysis Conclusions
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Ra-223 ongoing studies with combination regimen
73
Combination study Patient Phase Primary endpoint
Ra223 + Abiraterone Acetate mCRPC II Bone pain assessment & QoL
Ra223 + Abiraterone Acetate V.SPlacebo + Abiraterone Acetate
Pre-chemo III Symptomatic skeletal event free survival (SSE-FS)
Ra223 + Docetaxel V.S Docetaxel mCRPC I, II Dose escalation: ToxicityExpanded cohort: Safety
Ra223 +Enzalutamide mCRPC II Safety
Ra223 +Enzalutamide mCRPC II Bone formation markers at W11, 19, and 26
Ra223 V.S Ra223 + Abiraterone Acetate or Enzalutamide
mCRPC IIa Bone scan response at W24
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Ongoing trial in Taiwan
International, multicenter, randomized, open-label phase II study.
3 treatment arms in 1:1:1 fashion: ◦50 kBq/kg IV every 28 days for up to 6 doses ◦80 kBq/kg IV every 28 days for up to 6 doses ◦50 kBq/kg IV every 28 days for up to 12 doses
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Thanks For Your Attention