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ACRIN 6682 Phase II Trial OF 64 Cu-ATSM PET/CT in Cervical Cancer Principal Investigator: Farrokh Dehdashti, MD. 10/4/08. Is Hypoxia Clinically Relevant?. Clinically relevant levels of hypoxia detected in 50–60% of all solid tumors, irrespective of size and histopathological features

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  1. ACRIN 6682Phase II Trial OF 64Cu-ATSM PET/CT in Cervical CancerPrincipal 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. Is Hypoxia Clinically Relevant? • Several hypoxia-targeted therapies, including hyperbaric O2 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

  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. 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 Hypoxia: Cervical Cancer

  6. 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) Measurement of Hypoxia with Cu-ATSM

  7. PET Imaging Agents – Cu(ATSM) Theory: H3C CH3 H3C CH3 NOT TRAPPED H3C CH3 H3C CH3 TRAPPED N N N N N N N N N N N N Cu N N N N Cu Cu S S SH HS HN NH HN NH Cu S S S S HN NH HN NH CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 Hypoxic cell (-O2) Normal cell (+O2) Basic Science: Single Cell Suspension Assay PET Imaging of Tumor-Bearing Rodent Hypoxic Tumor Hypoxic Cells IMAGEABLE DIFFERENCE Uptake Uptake Normal Cells NormoxicTumor Time Time

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

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

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

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

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

  13. ACRIN 6682 Endpoints • Primary endpoint: to assess the relationship between 64Cu-ATSM uptake in the primary cervical tumor and progression-free survival after chemoradiotherapy. • Secondary endpoints: to assess the relationship between 64Cu-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

  14. ACRIN 6682 Eligibility • 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

  15. ACRIN 6682 Status • 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

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