Radiopharmaceutical Therapy with Radium-223 and 131 I-mIBG

Transcription

1 Radiopharmaceutical Therapy with Radium-223 and 131 I-mIBG Aaron C. Jessop, MD, MBA Associate Professor of Clinical Radiology Director of Nuclear Medicine and PET Vanderbilt University Medical Center

2 Target Audience: Pharmacists ACPE#: L01-P Activity Type: Knowledge-based Target Audience: ACPE#: Activity Type:

3 Disclosures Financial: None 131 I-mIBG is not FDA approved for Therapy The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

4 Learning Objectives 1. To understand clinical indications and utilization of radium-223 dichloride therapy 2. To understand research applications and benefits of 131 I- MIBG Target therapy Audience: for neuroblastoma: 3. To understand research applications and benefits of 131 I- ACPE#: MIBG therapy for metastatic pheochromocytoma & paraganglioma Activity Type:

5 1. Assessment Question 1. What is an approved indication for Radium-223 therapy in the United States? A. Metastatic cancer to the liver. B. Metastatic Target Audience: cancer of any origin to bone C. Metastatic castration-resistant prostate cancer to bone D. Cosmesis ACPE#: Activity Type:

6 2. Assessment Question 1. Which is an FDA-approved indication for 131 I-MIBG therapy in the United States A. Metastatic neuroblastoma refractory to chemotherapy B. Metastatic Target Audience: malignant pheochromocytoma C. Metastatic malignant paraganglioma D. 131 ACPE#: I-MIBG is not currently FDA approved for therapy Activity Type:

7 Radionuclide Therapy for Metastatic Prostate Cancer Palliative Benefit Survival Benefit

8 Bone-Seeking Radiopharmaceuticals Tu SM et al. Clin Adv Hematol Oncol May;8(5):

9 Radionuclides - Palliative Therapy for Bone Metastases

10 Radium Alkaline Earth Metal Ra-226 Discovered in 1898 by Marie and Pierre Curie Radioluminescent properties Images:

11 N Engl J Med Jul 18;369(3):

12 Ra-223 and Survival in Metastatic Prostate Cancer Ra-223 vs. Placebo 921 Patients Six injections of Ra-223 (50 kbq/kg) or Placebo every 4 weeks Plus standard of care Primary endpoint: Overall Survival Secondary Endpoints: First symptomatic skeletal event Biochemical markers N Engl J Med Jul 18;369(3):

13 N Engl J Med Jul 18;369(3):

14 N Engl J Med Jul 18;369(3):

15 N Engl J Med Jul 18;369(3):

16 N Engl J Med Jul 18;369(3):

17 Ra-223 Clinical Use FDA Approved in 2013 (Radium-223 dichloride - Xofigo) Indication: Castration-resistant prostate cancer Symptomatic bone metastases No known visceral metastatic disease Dosage and Administration: 55 kbq (1.49 microcuries) per kg body weight 4 week intervals for 6 injections Administration: Sow intravenous injection over 1 minute Saline flush before and after injection Ra-223 Dichloride (Xofigo) Package Insert

18 Ra-223 Patient Selection Metastatic Castrate-Resistant Prostate Cancer (MCRPC) Bone metastases Confirmed on radionuclide bone scan No known visceral metastases Such as lung or liver (CT) Not on cytotoxic chemotherapy

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21 Ra-223 Hematologic Evaluation Baseline prior to initial therapy: Hemoglobin: 10 g/dl Absolute Neutrophil Count (ANC): 1.5 x 109/L Platelet Count: 100 x 10 9 /L Values prior to subsequent therapies (2-6): Absolute Neutrophil Count (ANC): 1.0 x 109/L Platelet Count: 50 x 10 9 /L

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23 Ra-223: Future Developments Research questions Utilization with concurrent chemotherapy More than one course (6 administrations) of Ra-223 Use in other malignancies

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25 131 I-MIBG Therapy Overview mibg Targeted radiotherapy for neuroblastoma Metastatic pheochromocytoma/paraganglioma 131 I-Ultratrace Iobenguane

26 MIBG Metaiodobenzylguanidine Iobenguane mibg MIBG Adreview Ultratrace Iogenguane 131 I Azedra

27 MIBG Metaiodobenzylguanidine Guanethidine derivative Sympathetic blockade reduces release of catecholamines Resembles norepinephrine Taken up by cells in the sympathomedullary system Adrenal medulla

28 Neuroblastoma Infants and young children Most common extracranial solid tumor 650 cases annually in the United states Median age at diagnosis: 15 months

29 Neuroblastoma Primary tumor of sympathetic nervous system Neuroblastic Tumors Occur anywhere along the sympathetic chain Neck to Pelvis Most common sites are abdominal Adrenal Gland Higher risk than intrathoracic tumors By OpenStax College - Anatomy & Physiology, Connexions Web site. Jun 19, 2013., CC BY 3.0,

30 Neuroblastoma 40% Adrenal 15% Abdominal (extra-adrenal) 5% Cervical 5% Pelvic Sympathetic ganglia By OpenStax College - Anatomy & Physiology, Connexions Web site. Jun 19, 2013., CC BY 3.0,

31 Neuroblastoma & Paraganglioma Graphic Version 2.0

32 Neuroblastoma Prognosis Varies significantly Spontaneous regression Aggressive metastases Risk Classifications (The Children s Oncology Group) Low, Intermediate, High Poor prognostic factors Age (>18 months) Advanced stage MYCN oncogene amplification Poorly differentiated or undifferentiated histology

33 Probability of event-free survival based on COG risk stratification Parisi MT et al. Semin Nucl Med May;46(3):

34 Neuroblastoma Metastases 50% present with metastases Bone marrow Cortical bone Distant lymph nodes Liver Parisi MT et al. Semin Nucl Med May;46(3):

35 Neuroblastoma Therapy with 131 I-MIBG Investigational Part of clinical trials since the 1980 s Parisi MT et al. Semin Nucl Med May;46(3):

36 Neuroblastoma Therapy with 131 I-MIBG Single Agent Therapy Combined with autologous stem cell transplant Combination therapies Part of first-line treatment

37 Neuroblastoma Single Agent Therapy Matthay KK et al. J Clin Oncol Mar 20;25(9):

38 Neuroblastoma JCO 2007 Patients Progressive, refractory or relapsed high-risk neuroblastoma Age 2 to 30 years Treatment Cryopreserved hematopoietic stem cells 18 mci/kg (n=148) No cryopreserved hematopoietic stem cells 12 mci/kg (n=16) Matthay KK et al. J Clin Oncol Mar 20;25(9):

39 Neuroblastoma JCO 2007 Results: Overall response rate (complete + partial): 36% Overall survival 1 year: 49% 2 years: 29% Event-free survival 1 year: 18% Higher response rate Disease limited to either bone and bone marrow or soft tissue (not both) Fewer than 3 prior treatment regimens Patients older than 12 years Matthay KK et al. J Clin Oncol Mar 20;25(9):

40 Neuroblastoma JCO 2007 Matthay KK et al. J Clin Oncol Mar 20;25(9):

41 Neuroblastoma I-MIBG Therapy + ASCT In combination with autologous SCT 131 I-MIBG + high-dose chemo + autologous SCT Goals: Maximize therapeutic effect Avoid development of resistant tumor clones

42 Neuroblastoma I-MIBG Therapy + ASCT Yanik GA et al. Biol Blood Marrow Transplant Apr;21(4):673-81

43 Neuroblastoma I-MIBG Therapy + ASCT 2015 Phase II Clinical Trial 50 patients 131 I-MIBG (Day -21) Carboplatin, etoposide, melphalan (Days-7 to -4) Autologous Stem Cell Transplant (Day 0) 131 I-MIBG Dosing 12 mci/kg if GFR 100 ml/minute/1.73 m 2 8 mci/kg if GFR 60 to 99 ml/minute/1.73 m 2 Cohort 1 - higher risk Refractory (n=27)or progressive (n=15) disease Cohort 2 Partial response to induction therapy (n = 8) Yanik GA et al. Biol Blood Marrow Transplant Apr;21(4):673-81

44 Neuroblastoma I-MIBG Therapy + ASCT Yanik GA et al. Biol Blood Marrow Transplant Apr;21(4):673-81

45 Neuroblastoma I-MIBG Therapy + ASCT EFS at 3 years Cohort 1 = 20% Cohort 2 = 38% OS at 3 years Cohort 1 = 62% Cohort 2 = 75% Yanik GA et al. Biol Blood Marrow Transplant Apr;21(4):673-81

46 Neuroblastoma Part of First-line Treatment Goals Reduce volume of primary tumor Enable adequate surgical resection Reduce number of malignant cells at metastatic sites Avoid toxicity associated with chemotherapy Reduce early induction of drug resistance. de Kraker J et al. Eur J Cancer Mar;44(4):551-6.

47 Neuroblastoma Part of First-line Treatment 41 Patients Newly diagnosed high risk First infusion 200 mci (7.4 GBq) Second infusion 150 mci ( GBq) (4 weeks) 24 Patients CR or PR Surgical resection 17 patients SD Chemotherapy before tumor resection Four courses of chemotherapy following surgery Stem cell transplantation Consolidation therapy for 6 months Overall induction response rate: 73% de Kraker J et al. Eur J Cancer Mar;44(4):551-6.

48 Neuroblastoma 131 I-MIBG Therapy Toxicity Early Nausea, emesis, hypertension, parotitis Intermediate (weeks) Myelosuppression transfusions, stem cell support Late (months) Hypothyroidism, MDS, AML Parisi MT et al. Semin Nucl Med May;46(3):

49 Neuroblastoma Therapy with 131 I-MIBG Single Agent Therapy Combined with autologous stem cell transplant Combination therapies Part of first-line treatment

50 Post-Therapy 131 I-MIBG Imaging Sharp SE et al. Radiographics Jan-Feb;36(1):

51 Multicenter Trial at VUMC AN OPEN LABEL, EXPANDED ACCESS PROTOCOL USING131I- METAIODOBENZYLGUANIDINE (131I-MIBG) THERAPY IN PATIENTS WITH REFRACTORY NEUROBLASTOMA, PHEOCHROMOCYTOMA, OR PARAGANGLIOMA

52 MIBG Therapy Multicenter Trial Refractory or relapsed Neuroblastoma Pheochromocytoma or paraganglioma Not amenable to surgery >12 months of age Failure to respond to standard therapy Or development of progressive disease

53 MIBG Therapy Multicenter Trial Refractory or relapsed Neuroblastoma Pheochromocytoma or paraganglioma Not amenable to surgery >12 months of age Failure to respond to standard therapy Or development of progressive disease

54 Pheochromocytoma Stem cells: Patients must have a hematopoietic stem cell product available for reinfusion after 131I-MIBG treatment at doses of 12 mci/kg. The minimum quantity for purged or unpurged peripheral blood stem cells (PBSC) is 1.5 x 106 viable CD34+ cells/kg (recommended 2 x 106 viable CD34+ cells/kg). The minimum number may be met by combining different types of stem cell products as listed below (ie: purged + unpurged PBSC). The minimum dose for bone marrow is 1.0 x 108 mononuclear cells/kg (optimum > 2.0 x 108 mononuclear cells/kg).

55 MIBG Therapy Multicenter Trial 24 month old female Diagnosed 1 year previously Biopsy of L temporal lesion Left adrenal primary Metastases to the skull, right humerus, right femur Chemotherapy, ASCT, Radiation Therapy 9 months later relapse in left leg Chemo, Radiation

56 Outside I-123 MIBG (2 hour)

57 Outside I-123 MIBG (24 hours)

58 Post-Therapy Imaging (24 hours)

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60 Paraganglioma Extra-adrenal locations Autonomic paraganglia Most benign Malignant degeneration 10-20% Sympathetic paragangliomas Secrete catecholamines Sympathetic paravertebral ganglia Thorax, Abdomen, Pelvis Parasympathetic paragangliomas Most nonfunctional Glossopharyngeal and vagal nerves Neck and base of skull By OpenStax College - Anatomy & Physiology, Connexions Web site. Jun 19, 2013., CC BY 3.0,

61 54 Year-old male Unintentional weight loss Vague abdominal symptoms

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64 Malignant Pheochromocytoma/Paraganglioma Malignant disease Presence of metastatic lesions Sites where neuroendocrine tissue is normally absent Prognosis Poor Treatments primarily palliative Overall 5-year survival <50%

65 Malignant Pheochromocytoma/Paraganglioma 56 year-old female Malignant pheochromocytoma 123 I-MIBG Imaging

66 MIBG Therapy for MPP van Hulsteijn LT et al. Clin Endocrinol (Oxf) Apr;80(4):

67 MIBG Therapy for MPP Meta Analysis 17 separate studies patients Malignant pheochromocytoma or paraganglioma Mean follow-up 24 to 62 months van Hulsteijn LT et al. Clin Endocrinol (Oxf) Apr;80(4):

68 MIBG Therapy for MPP Meta Analysis Wide range of cumulative activity 186 1,065 mci (6,882 39,400 MBq) Median number of infusions Range 1-7 van Hulsteijn LT et al. Clin Endocrinol (Oxf) Apr;80(4):

69 van Hulsteijn LT et al. Clin Endocrinol (Oxf) Apr;80(4):

70 van Hulsteijn LT et al. Clin Endocrinol (Oxf) Apr;80(4):

71 MIBG Therapy for MPP Meta Analysis Complete response: 3% Partial response: 27% Stable disease: 52% 82% van Hulsteijn LT et al. Clin Endocrinol (Oxf) Apr;80(4):

72 MIBG Therapy for MPP Adverse Effects Well tolerated at lower doses Nausea Vomiting Anorexia Mild leukopenia Mild Thrombocytopenia

73 MIBG Therapy for MPP Adverse Effects High doses have higher risk of serious adverse effects Grade 3-4 thrombocytopenia and neutropenia Myelodysplastic syndrome Acute myeloid leukemia Hypothyroidism Pretreat with inorganic iodine Potassium iodide beginning 24 hours prior to therapy Continue for 10 days

74 MIBG Therapy for MPP High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma Median cumulative activity 1,015 mci Complete response: 3 patients Two with soft tissue and skeletal metastases Partial response: 7 patients Progressive disease: 2 patients Side effects Grade 3 thrombocytopenia: 79% of treatments Grade 3 neutropenia: 53% Grade 4 neutropenia: 19% Rose B, Matthay KK, Price D, et al. Cancer 2003;98:

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76 Ultratrace Iogenguane Ultratrace Iobenguane 131 I High specific-acitivty form of 131 I-MIBG Different labeling approach Non-carrier-added radiolabeled MIBG Norepinephrine transporter uptake Competitive process Cold MIBG can diminish 131 I-MIBG uptake

77 Ultratrace Iogenguane Carrier molecule Does not contribute to therapeutic response Bioactive Hypertension Nausea Vomiting Animal models Higher levels of radioactivity in target tissue Greater therapeutic efficacy Less appreciable cardiovascular side effects Barrett JA, Joyal JL, Hillier SM, et al. Cancer biotherapy & radiopharmaceuticals 2010;25:

78 Ultratrace Iogenguane Clinical Trial Multicenter including MDACC Phase II study Effectiveness and safety of Ultratrace Iobenguane 131 I Malignant pheochromocytoma/paraganglioma Primary outcome measure Reduction of antihypertensive medication by at least 50% for at least six months or two cycles of Ultratrace Iobenguane 131 I Secondary measures Complete or partial response by RECIST (24 months) Overall survival Safety (labs, physical exam, vitals) Quality of life

79 Ultratrace Iogenguane Clinical Trial 5 mci Ultratrace Iobenguane 131 I Confirm MIBG-avidity Dosimetry 500 mci (or 8 mci/kg if 62.5 kg or less) 3 months Second infusion 500 mci (or 8 mci/kg)

80 Ultratrace Iobenguane 131 I Case Example 34 year-old male Presented with back pain Found to have paraganglioma Originating at organ of Zuckerkandl Invading bone Increased normetanephrines

81 Ultratrace Iobenguane 131 I Dosimetry 0-1 hour 1-2 Day 2-5 Day

82 Ultratrace Iobenguane 131 I Post-Therapy Cumulative 1,049 mci Post- Therapy 1 Post-Therapy 2

83 Ultratrace Iobenguane 131 I Case Example One year follow-up Improvement in hypertension Improvement in pain Decrease size of retroperitoneal mass

84 Conclusion Radium-223 dichloride therapy Survival benefit in metastatic prostate cancer to bone Palliative benefit FDA-approved and in clinical use 131 I-MIBG Therapy Neuroblastoma Malignant pheochromocytoma/paraganglioma Investigational Shown to be effective in multiple clinical trials

85 1. Assessment Question 1. What is an approved indication for Radium-223 therapy in the United States? A. Metastatic cancer to the liver. B. Metastatic Target Audience: cancer of any origin to bone C. Metastatic castration-resistant prostate cancer to bone D. Cosmesis ACPE#: Activity Type:

86 2. Assessment Question 1. Which is an FDA-approved indication for 131 I-MIBG therapy in the United States A. Metastatic neuroblastoma refractory to chemotherapy B. Metastatic Target Audience: malignant pheochromocytoma C. Metastatic malignant paraganglioma D. 131 ACPE#: I-MIBG is not currently FDA approved for therapy Activity Type: