USE OF RADIONUCLIDE THERAPY: ACTUAL CLINICAL APPLICATIONS?

Zurich, 2010

J. Boratynski R. Kristensen F. Bruchertseifer

Outline
1. Aim of radionuclide therapy 2. Radionuclides for therapy parameters and characteristics. 3. Linkers parameters and characteristics. 4. Carriers parameters and characteristics. 5. Examples. 6. Future/Clinical Trials. 7. Summary.

Aim of radionuclide therapy

The fundamental objectives for radionuclide therapy are: 1. To achieve appropriate treatment of the disease through delivery of a radiation dose at the desired cytotoxic level with the defined endpoints being cure, disease control (stabilization) or palliation. 2. To avoid or minimize toxic effects (spare normal organs), both in the acute time frame and as long term complications. The goal of radionuclide therapy is to maximize the therapeutic index as represented by the ratio of the radiationdose delivered to the tumor to that delivered to normal tissue.

S.R. Thomas, Cancer Biotherapy & Radiopharmaceuticals, 2002, 17, 1, p.71

Structure
Target Carrier
Linker

Radionuclide

Carriers: Monoclonal antibodies, Peptides (somastotatin analogues), Small molecules (sugars, amino acids), Liposomes, Microspheres, Particles Linkers: DOTA, NOTA, TRITA, DTPA Radionuclides:
90Y, 177Lu, 186Re, 131I, 153Sm 211At, 212Bi 193mPt

Auger

Radionuclides for therapy parameters and characteristics

- stable daugher isotope
- a proper type of radiation (, Auger electrons, ) - apropriate physical half-life time (hours, days) - radiation energy + high LET (effective cell irradiation ~300 keV) - range of radiation: Auger electrons ~ nm ~ m ~ mm

Linkers parameters and characteristics

- conjugate metal and carrier bifunctional - chelate metal - couple with carrier - stable in-vivo conditions (kinetically inert)

Carriers parameters and characteristics

- reach matastases via blood stream - relatively long biological half-life time - stable in-vivo

non-Hodgkins lymphoma (NHL)

Target: CD20 receptor on mature b-cells Pre-treatment: rituxan (naked antibody) clearing the majority of normal b-cells - the therapeutic radiolabeled antibody is more focused on tumor cells. Mechanism: the monoclonal antibody recognizes and attaches to the CD20 antigen, allowing radiation emitted by radioisotope to penetrate and damage the B-cell as well as neighboring cells. Zevalin: 90Y T1/2=2.7 d Energy: 2,28 MeV Bexxar: 131I T1/2=8 d Energy: 600 keV , 364 keV
[http://www.lymphomation.org/compare-bexxar-zevalin.htm]

Zevalin

Bexxar

Neuroendocrine tumours

177Lu-DOTATATE, 177Lu-DOTATOC 90Y-DOTATATE, 90Y-DOTATOC

Target: somatostatin receptors. The somatostatin receptor is strongly over-expressed in most tumours, resulting in high tumour-to-background ratios. 25% of patietns achieving objective tumour shrinkage >50%. Serious side-effects have been rare. 90Y T1/2=2.7 d Energy: 2,28 MeV
177Lu

T1/2=6,7 d Energy: 497 keV , 208 keV

F. Forrer et al., Best Practice & Research Clinical Endocrinology & Metabolism, 2007, 21,1, p. 111-129

Thyroid carcinoma
Na131I in capsules and i.v. (also diagnosis) target: thyroid mechanism: thyroids iodine uptake the oldest and most succesful radiopharmaceutical since: 40

T1/2=8 d Energy: 600 keV , 364 keV

Phaeochromacytoma & Neoblastoma

131I-mIBG I-mIBG

Similar to norepinephrine Uptake by adrenergic receptors 123I 159 keV & 27 keV 131I 606 keV 89% Incidence Phaeochromacytoma 2-8/106 pr. Year Neoblastoma 2/106 pr. Year

norepinephrine

Phaeochromacytoma & Neoblastoma

40 patients received 131I-MIBG therapy. May 1996 to May 2006 Strong uptake of 123I-MIBG, by Scintigraphy. 7.4 GBq pr. treatment cycle. Average 1.8 cycles. 11 patients showed reduction in tumour size post-therapy. 27 patients reported improved symptoms after 131I-MIBG therapy. 11 patients required hospitalisation as a consequence of complications (bone marrow suppression). Median survival increased by 37 months (symptomatic responders). I-mIBG

norepinephrine

Nwosu et al. British Journal of Cancer (2008) 98, 1053 1058

Synoviorthesis

90Y-Colloid

For Rheumatoid Arthritis, Osteoarthritis and others. Mainly used in knee's. In practice since the 60's. Principle: The colloidal particles are phagocytized by the synovial lining cells. The energy released effects a therapeutically active irradiation of the surrounding synovial tissue, resulting in a fibrotic and sclerosed synovial membrane. The inflammatory and destructive processes is stopped, which leads to an alleviation of the pain and effision, followed by an occlusion of superficial capillaries. 90Y citrate or silicate colloid 111222MBq.

Hydroxyapatite particles (HA)

90YCI 3

Synoviorthesis
Review of articles from 19752006. (Medline, Embase, Biosis, Derwent Drug file, SciSearch) Conclusions: Minimally invasive therapy. Treatment is efficacious In view of benefits, tolerability and safety are very good Important! Post-treatment immobilization and the co-administration of corticoids, to minimize the risk of leakage and of efflux through the puncture channel.

Hydroxyapatite particles (HA)

90YCI 90YCI3 3

Review article by Kampen et al.,Rheumatology 2007;46:1624

Hepatoma
90Y-

micro Particle

TheraSphere - Glass particles Sirtex - Polymer particles Principle: Solid particles are inserted into the hepatic artery of the tumor, cause embolisation in the tumor microvasculature and tumor irradiation. Normal liver parenchyma is predominantly supplied with blood from the portal vein. Gastric Mucosa

Sirtex particles

Hepatoma
30 patients Jan 2002Mar 2004 Hepatic metastasis from colorectal cancer
Gastric Mucosa

Sirtex particles
Lim et al. BMC Cancer 2005, 5:132 doi:10.1186/1471-2407-5-132

Bone Metastasis

153Sm-EDTMP

Ethylenediamine tetra(methylene phosphonic acid) Approved for palliative treatment in the USA since 1998 Standard palliative dose 1mCi/kg T=46,27h Bind to Ca2+

Bone Metastasis
Review of: Three randomized phase III trials, Two randomized phase II trials Metastatic Breast prostate and lung cancer. Conclusion: Samarium-153 should be considered as a possible option for the palliation of multiple sites of bone pain from metastatic cancer where pain control with conventional analgesic regimens is unsatisfactory and where activity on a bone scan of the painful lesions is demonstrated. Ongoing clinical research should seek to establish the benefit of newer radiopharmaceuticals and radiopharmaceuticals in combination with other systemic therapies
Bauman et al. Radiotherapy and Oncology 75 (2005) 258.e1258.e13

clinical trials - At-211-MX35 F(ab)2

[phase I]

Aim: - to determine the relevant pharmacokinetics for assessing absorbed dose to normal tissues and investigating the toxicity Methods: -appr. 500 MBq of 211At was labeled to 0.7 mg of MX35 F(ab)2 using the reagent N-succinimidyl 3(trimethylstannyl) benzoate - 50 MBq (3 patients) or 100200 MBq (6 patients) in 12 L of Extraneal was infused via the peritoneal catheter Results: - At-211 was found peritoneal fluid, serum (to 6% IC after 30 h) and thyroid to 127 63% at 20 h without blocking < 20% IC with blocking - no other organ uptakes could be detected - estimated absorbed dose to the peritoneum was 15.6 1.0 mGy/(MBq/L) - no adverse effects were observed either subjectively or in laboratory parameters Conclusion: - intraperitoneal administration of 211At-MX35 F(ab)2 it is possible to achieve therapeutic absorbed doses in microscopic tumor clusters without significant toxicity

Andersson et al, Journal of Nuclear Medicine 2009;50:11531160

clinical trials - I-131-Labetuzumab

[phase I/II]

Aim: - RIT using I-131 labetuzumab (anti-CEA) after the salvage resection of colorectal (CRC) liver metastases (LMs) - liver is the only metastatic site in 30%40% of CRC patients - 5-year survival rate is 0%3% Method: -40-60 mCi/m I-131 labetuzumab -2x40-50 mCi/m I-131 labetuzumab Outcome: Safe, feasible, well accepted Prologed survival time Phase III

Liersch T, et al Ann Surg Oncol 2007;14:2577

clinical trials - Lu-177/Y-90 PRRT

Aim: - peptide radioreceptor therapy (PRRT) with Lu-177/Y-90 for neuroendocrine tumors - peptide [DOTA0,Tyr3]octreotide (DOTATOC) and [DOTA0,Tyr3]octreotate (DOTATATE), specific for somastotatine receptors Method: - 3 +/- 2 GBq Y-90 peptide - 7 +/- 3 GBq Lu-177 peptide Outcome: According WHO criteria - CR 2% - PR (more 50%) 22% - PR (25% - 50%) 12% - SD 49%
http://www.carcinoid-call-point.de/assets/Patienteninformation_RRT_fuer_INTERNET_2006-08.pdf D. J. Kwekkeboom et al, Eur. J. Nucl. Med. Mol. Imag. 30/2003, 417-22 Waldherr C et al, Ann Oncol. 2001 Jul;12(7):941-5 Frilling et al, Surgery, 2006, 140(6), 969

clinical trials - Ac-225/Bi-213 CD33

Phase I:

[phase I/II]

18 patients with relapsed and refractory AML (acute myelogenous leukemia) or CML (chronic myelomonocytic leukemia) 0.3 - 1.0 mCi/kg body weight of 213Bi-HuM195 (anti-CD33) no significant toxicity 14/18 patients responded
J. Jurcic, Blood 2002

Phase I/II (ongoing): elimination of residual disease after partial cytoreduction using cytarabine > 30 AML patients treated so far 0.5 1.25 mCi/kg body weight of 213Bi-HuM195 MTD 1 mCi/kg 24% of patients receiving 1 mCi/kg (n=25) responded (2 CR, 2 CRp, 2PR)
T. Rosenblatt et.al. submitted

clinical trials - Glioma/Glioblastoma

At-211-labeled chimeric antitenascin antibody, 81C6 Outcome: - 97% of At-211 occurred in the surgical resection cavity - survival increased to 52 weeks in glioblastomas and 97 weeks in nonglioblastoma tumors 77 - historic control of 31 weeks - limitation in the specific activity

[phase I]

Zalutsky et al J Nucl Med 2008;49:30

Substance P labelled with Lu-177/Bi-213 (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH-R) Outcome: - only transient toxicity was seen as symptomatic radiogenic edema in one patient - disease stabilization and/or improved neurologic status was observed in 13 of 20 patients - resection disclosed widespread radiation necrosis with improved demarcation TAT with diffusible peptidic vectors for local control of malignant gliomas
Kneifel et al Clin Cancer Res. 2006 Jun 15;12(12):3843-50

clinical trials - melanoma

[preclinical/phase I]

Rhenium-188 - Re-188 sulfur colloid, tin colloid or microspheres on carrier e.g. filter paper, emulsion - doses appliceted 50 to 100 Gy Jeong et al, Appl RadiatIsot 2003;58:551

Bismuth-213 - Phase I study on grade IV malignant melanoma / in-transit metastases using Bi-213 labelled mAb 9.2.27 Results: 48 patients treated with 1.5 to 27 mCi Bi-213-9.2.27 - 12% partial response - 50% stable disease - 38% progressive disease - no signs of adverse effects C. Raja et al, Cancer Biology & Therapy 6:6, 846-852; 2007

Summary
- long tradition of radionuclide therapy - radionuclide therapy especially the radioimmunonuclide therapy large potential - use of beta and alpha emmiting radionuclides e.g. Y-90, I-131, Sm-153, Lu-177, Re-186/188, At-211, Bi-213 etc. -commercially used vectors e.g. Zevalin, Bexxar, EDTMP, HDEP -Variety of clinical trials with further AB and peptides e.g. CD33, Labetuzumab, Substance P, DOTATOC, DOTATATE

Outlook
- more specific targeting - use of alternative radionuclides specifically for the type of tumors ( or Augeremiters) - combination of antibodies and peptides (pre-targeting) e.g. modified CD22 with IMP-288 (B-cell cancer)

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