1. ACRIN 6682 Phase II Trial OF 64 Cu-ATSM PET/CT in Cervical Cancer Principal Investigator: Farrokh Dehdashti, MD 10/4/08

2. Is Hypoxia Clinically Relevant? Clinically relevant levels of hypoxia detected in 50–60% of all solid tumors, irrespective of size and histopathological features Hypoxia stimulates expression of many genes to activate processes such as angiogenesisis and is associated with tumor progression, increased aggressiveness, enhanced metastatic potential, and poor prognosis Hypoxia increases resistance to radiation therapy and chemotherapy

3. Several hypoxia-targeted therapies, including hyperbaric O 2 breathing, radiosensitizers, and hypoxic cytotoxins, have been developed to overcome hypoxia-mediated radio/chemoresistance –Increased tumor control rate is often accompanied by more severe side effects –Development of methods for prediction of tumor response and early monitoring of treatment responses could reduce both over- and under-treatment, thereby avoiding unnecessary side effects Is Hypoxia Clinically Relevant?

4. Detection of Hypoxia Hypoxic-measuring tools are needed: –To predict patient outcome –To select treatments on an individual basis –To evaluate early response to treatment

5. Hypoxia: Cervical Cancer Höckel et al. –Pretreatment tumor hypoxia (as measured by oxygen electrodes) was associated with decreased survival rate and pelvic failures –Oxygen status of the tumor was the single most important prognostic factor, independent of various patient demographics and pretreatment tumor characteristics Pitson, Fyles et al. –Tumor hypoxia was an adverse prognostic factor and significantly increased the risk of regional and distant metastases

6. Measurement of Hypoxia with Cu-ATSM Copper labeled dithiosemicarbazone complex (Cu-ATSM) ( Fujibayashi et al.,1989, 1997; John et al., 1990; Taniuchi et al., 1995 ) –Highly lipophilic - high membrane permeability - high extraction –Reduced by bioreductive enzymes* only in hypoxic cells (mitochondria in non-tumor and microsomal/cytosol in tumors) –Retained in hypoxic tissues, but rapidly washes out of normoxic tissue –Good hypoxic/normoxic tissue activity ratio (hypoxic/normoxic of 4.0 at 15 min)

7. PET Imaging Agents – Cu(ATSM)

8. 38 patients undergoing radiotherapy  chemotherapy Pre-therapy 60 Cu-ATSM-PET (tumor/muscle ratio) Response to therapy assessed (follow-up 3-79 months) 60 Cu-ATSM: Cervical Cancer Dehdashti et al., JNM 2008; 49:210

9. 60 Cu-ATSM: Cervical Cancer FDG 60 Cu-ATSM T/M = 3.0 Responder T/M = 4.5 Non-responder Dehdashti et al., JNM 2008; 49:210

10. 60 Cu-ATSM: Cervical Cancer Dehdashti et al., JNM 2008; 49:210

11. 60 Cu vs 64 Cu-ATSM: Cervical Cancer Lewis, et al., JNM 2008; 49:1177 Half-life 60 Cu 23.7 min 64 Cu 12.7 hr

12. Pre-therapy clinical whole-body FDG-PET/CT Pre-therapy pelvic 64 Cu-ATSM-PET/CT analysis of tumor biopsy for hypoxic markers ACRIN 6682 Schema Concurrent chemoradiotherapy Clinical FDG-PET/CT three (3)-months after completion of therapy Clinical follow-up for detection of recurrence and/or death

13. Primary endpoint: to assess the relationship between 64 Cu- ATSM uptake in the primary cervical tumor and progression- free survival after chemoradiotherapy. Secondary endpoints: to assess the relationship between 64 Cu-ATSM uptake and: –overall survival –rates of local recurrence and development of distant metastasis –frequency of complete metabolic response by FDG-PET –tumor volume and the frequency of lymph node metastasis at diagnosis –markers of tumor hypoxia assessed by immunohistochemistry on biopsy tissue from the primary tumor ACRIN 6682 Endpoints

14. Women with stages IB2 –IVA, histologically confirmed, invasive squamous cell cervical carcinoma, who are scheduled to undergo radiation therapy and concurrent cisplatin chemotherapy Sample size: 100 ACRIN 6682 Eligibility

15. Protocol finalized and reviewed by CTEP Responses to additional CTEP questions submitted 9/26/08 Still need to submit amendment to WU IND for this new protocol and to change compounding to a kit formulation method (pending DMF from vendor) Site qualification and contracting pending –Potential sites: Duke Univ., FCCC, JHMI, Mayo Clinic, MDACC, MKSCC, Univ. of Iowa, Vanderbilt Univ., WU ACRIN 6682 Status