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Herceptin as a Phase 0 Imaging Example. Phase 0 Trials in Oncology Drug Development

Herceptin as a Phase 0 Imaging Example. Phase 0 Trials in Oncology Drug Development. Steven M. Larson, M.D. Nuclear Medicine Svc, Department of Radiology MSKCC, NY, NY. We are experiencing a paradigm shift.

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Herceptin as a Phase 0 Imaging Example. Phase 0 Trials in Oncology Drug Development

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  1. Herceptin as a Phase 0 Imaging Example. Phase 0 Trials in Oncology Drug Development Steven M. Larson, M.D. Nuclear Medicine Svc, Department of Radiology MSKCC, NY, NY

  2. We are experiencing a paradigm shift From anatomic towards biomarker (molecular imaging) as the primary means of assessing treatment response in Oncology

  3. Biomarkers • Biomarkers are biologic indicators of disease or therapeutic effects, which can be measured through dynamic imaging tests, as well as tests on blood, tissue and other biologic samples. • (Oncology Biomarker Qualification Initiative (OBQI ), a joint enterprise of US FDA, NCI and CMS)

  4. PET/CT in Cancer Care: Combines 2 high resolution diagnostic imaging methods Positron Emission Tomography (PET) Biochemistry and Function Computerized Tomography (CT) Anatomy and Structure

  5. Discovery ST

  6. CT

  7. PET-CT

  8. Why Now, Why Biomarkers? • The search for biomarkers as endpoints of clinical trials to help reduce the growing cost of obtaining new drug approvals • Dissatisfaction with the classical anatomic based imaging methods for assessing treatment response assess such as WHO criteria, or RECIST • Growing evidence the FDG uptake is an important predictor for aggressive behavior of cancers

  9. Oncology Biomarker Qualification Initiative (OBQI) • “Biomarkers are indicators of disease or therapeutic effects, which can be measured through dynamic imaging tests, as well as tests on blood, tissue and other biologic samples” • NCI,FDA, CMS memorandum of understanding • Cooperate closely with industry • http://www.fda.gov/oc/mous/domestic/FDA-NCI-CMS.html

  10. Potential Benefit of Biomarkers in Clinical Trials • Determine if patient’s tumor is likely to respond at all to specific treatments • Assess after 1 or 2 treatments if a tumor is dying, even if it is not shrinking in size • Determine which patients are at high risk for their patient recurring after surgery • Efficiently evaluate whether an experimental therapy is effective for tumor treatment

  11. PET FDG as Biomarker Larson SM and Schwartz LH: 18F-FDG PET as a candidate for "qualified biomarker": functional assessment of treatment response in oncology.J Nucl Med. 2006 Jun;47(6):901-3.

  12. Imaging Treatment Response: tyrosine kinase inhibitors 18F-FDG in GIST tumors treated with Glivec, an bcr/abl,c-kit, PDGFR kinase inhibitor

  13. GI Stromal Tumor (Pre-therapy with STI-571) Feb 26, 2001 686140

  14. GI Stromal Tumor (Post-therapy STI-571) June 7, 2001 (CT May 4, 2001) 686140

  15. SUV Activity per unit volume Injected Activity/Body Wt* *also, lean body mass, BSA, etc

  16. PET imaging and Tumor Response920 citations in Medline* • Breast Cancer • NSCLC • Lymphoma • Esophageal • Gastric • Head and Neck • Brain Tumor • Etc. * Dec 3, 2004

  17. Combined Anatomic and Molecular Imaging* * Courtesy of Lawrence Schwartz

  18. New Candidate Biomarkers (2) • Proliferation Markers. • 18FLT • Amino acid transporter • 18FACBC • 18F-tyrosine • 18F-DOPA • Hypoxia and aberrant hif-1 alpha expression • 18FMISO • CA IX, 124I-cG250 • Growth factor expression • Her 2, 68Ga-Fab’2 Herceptin* • Apoptosis • 18F-annexin • Blood Flow • DCE MRI

  19. Exploratory IND Phase 0 testing

  20. Exploratory IND* • Determine whether a mechanism of action defined in experimental systems can also be observed in humans (a binding property of inhibition of an enzyme) • Provide important information on PK • Select the most promising compound from a group of candidates designed to interact with a particular therapeutic target in humans based on PK or PD properties *Guidance for Industry, Investigators and Reviewers.. Jan 2006 USFDA URL http://www.fda.gov/cder/guidance/7086fnl.pdf

  21. Exploratory IND • Studies can be performed at “Microdose” levels, i.e., <1/100th of a pharmacologic dose, or <100 mg, for biologicals, <30 nM • Toxicity studies in animals should be 100x the dose in humans administered on a BSA basis • observe for 14 days, weight, chem, heme • Necropsy @ 2 days for histopathology

  22. 68Ga (Fab’2) Herceptin Image target protein Her 2 receptor, non-invasively in vivo

  23. HSP 90 : a target for chemo Critical Chaperone Function e.g., Her 2, AR, AKT

  24. Ansamycins bind to the ADP\ATP switch site in Hsp90 O O Me O O Me O H CO OH 3 MeO N Me Me OMe H NH Geldanamycin (GM) 2 O H N O Me N H O O Me O NH OH 2 MeO Me Me OMe 17-AAG

  25. 17AAG/Herceptin Phase 1 Patient 306 5 April 2005 1 June 2005 HER2+ Breast cancer with active sites of disease including the lung and bone. Previously treated with 3 different trastuzumab-containing combinations, progressing on bevacizumab plus trastuzumab prior to enrollment on the trial. Confirmed PR by RECIST. Modi et al., Abstract 501, ASCO 2006

  26. Metastatic Breast Cancer Solit, Rosen et al A B A – heart B – left adrenal metastasis C – right kidney C 12/28/04 3/17/05

  27. Pharmacodynamics Targeted Therapies: Inhibition of signal transduction

  28. Imaging Her-2 Expression • 15-20% response in Breast Ca with anti-her2 monoclonal antibody, Herceptin • Ansamycins, which target HSP-90, induce Her-2 Degradation

  29. Imaging her-2 expression in vivo 68Ga-(Fab’2) herceptin Virtual Immunohistology (VIH): Non-invasive imaging of tumor antigen expression in the living organism Smith-Jones et al: Nat Biotech.. 2004 Jun;22(6):701-6.

  30. V V V V H H L L C C H H 1 1 C C k k C C 2 2 H H C C 3 3 H H V V V V V V V V H H H H V V V V V V L L L L L L L L L L V V V V V V H H H H H H V V V V V V L L L L L L V V V V V V H H H H H H C C C C 3 3 3 3 H H H H scFv scFv scFv scFv scFv scFv Diabody Diabody Diabody Diabody Diabody Diabody Minibody Minibody Minibody Minibody 28 28 28 28 28 28 kDa kDa kDa kDa kDa kDa ( ( ( ( ( ( scFv scFv scFv scFv scFv scFv ) ) ) ) ) ) ( ( ( ( scFv scFv scFv scFv - - - - C C C C ) ) ) ) 2 2 2 2 2 2 H3 H3 H3 H3 2 2 2 2 55 55 55 55 55 55 kDa kDa kDa kDa kDa kDa 80 80 80 80 kDa kDa kDa kDa Courtesy Anna Wu, City of Hope Med Courtesy Anna Wu, City of Hope Med Ctr Ctr Targeted Radiopharmaceutical Therapy • Antibody Forms • Intact Antibody • Fab’2 • Fab • sFv • Diabody (sFv)2 • Minibody V V V V H H L L C C H H 1 1 C C k k C C 2 2 H H Intact Intact Intact Intact Ab Ab Ab Ab F( F( F( F( ab’ ab’ ab’ ab’ ) ) ) ) 2 2 2 2 150 150 150 150 kDa kDa kDa kDa 120 120 120 120 kDa kDa kDa kDa C C 3 3 H H V V V V H H L L C C 3 3 H H Minibody Minibody ( ( scFv scFv - - C C ) ) H3 H3 2 2 80 80 kDa kDa Courtesy Anna Wu, City of Hope Med Courtesy Anna Wu, City of Hope Med Ctr Ctr

  31. Quantitation of Antigen In-Vivowith b+ Labeled Antibodies Uptake = D[Ag] 68Ga-(Fab’)2 anti-p185HER2 (humanized 4DT: Herceptin)

  32. MicroPET images obtained 3 hours post injection with 68Ga-F(ab)2-Herceptin in a mouse with a BT 474 breast tumor Pre Treatment T=0 hours Post 17 AAG Treatment T=24 hours

  33. Gallium-68 herceptin imaging of her-2

  34. Western Blot Analysis of HER2 Protein Expression by Tumors Recovered from Control Animals or Animals Treated with 17-AAG.

  35. Effect of 17-AAG on HER2 Protein expression by BT474 Breast Cancer Line Kd unchanged Bmax reduced by 80%

  36. Example of 68Ga-F(ab’)2-Herceptin imaging of a CWR22 Prostate Tumor in a Mouse

  37. ROI Analysis of 68Ga-F(ab’)2-Herceptin Uptake in a CWR22 Prostate Tumor After 17-AAG Treatment. Formation half-life 1.35 days

  38. Her 2 imaging: IRB #06-090 Akhurst et al. T T T PET: Her 2+ Breast CT: Temporal lytic lesion Pt. # 1. Her 2 + Breast Cancer, metastatic to skull

  39. Tumor Response in Skull

  40. Her 2 imaging: IRB #06-090 Akhurst et al. T FDG 68Ga Herscan Pt. # 5. Her 2 + Breast Cancer, metastatic to liver

  41. Dosimetry (Olinda) N=5; 10 mCi of 68Ga (Fab’2) Herceptin Kidney is the critical organ at 0.41 cGy/mCi Effective dose equivalent 0.063 +/- .006 cGy/mCi

  42. FDG AR CT FDHT FLT 68Ga-(Fab’2) herceptin Virtual Immunohistology (VIH): Smith-Jones et al: Nat Biotech.. 2004 Jun;22(6):701 HER-2 PET: Her 2+ Breast CT: Temporal lysis

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