Mountain States Cancer Conference Jennifer Diamond, MD Developmental Therapeutics and Breast Oncology University of Colorado Cancer Center

Transcription

1 Mountain States Cancer Conference 2010 Jennifer Diamond, MD Developmental Therapeutics and Breast Oncology University of Colorado Cancer Center

2 To understand the rationale and process for clinical drug trials in oncology To consider the role of patients and physicians in clinical research studies To introduce the Developmental Therapeutics/ Phase I program at UCCC

3 To establish the best treatment for a specific disease based on evidence, free from prejudice Establish data through a careful, highly regulated, multistep/multi staged process Treatment should be based on real data: not just what someone wants to sell you not just someone s gut feeling not a popularity contest or what gets the most air time in the media

4 Why we need new anti cancer treatments: To cure more people To control the disease in those living with cancer, longer and better To make treatment: More convenient Less unpleasant Safer and more specific

5 A new drug as a single agent A new drug + a standard treatment An old drug + and old drug the combination is what is experimental A new treatment on its own, or added into standard treatment,compared to standard treatment alone (randomized) standard treatment may be supportive care only open label or blinded Any combination of the above

6 Phases of trials staged evaluation I = first in human, toxicity and dose evaluation enrolls multiple tumor types, little chance of seeing true efficacy in any one tumor type unless biologically based II = disease specific, relapsed patients seeks response rate or evidence of activity in similar patients III = compare new treatment to standard of care if successful, new treatment may BECOME standard IV = post market surveillance

7 Mr A (colon) Mr B (lung) Mrs C (breast) hase I tudy hase II studies dose from phase I) 60 patients with lung cancer (lung phase II) 60 patients with breast cancer (breast phase II) hase III tudies randomized) Hundreds of patients with a particular tumor type comparing standard treatment to new treatment

8 Phase Open to Accrual Active Closed to Accrual Trials Total I/II II II/III III Enrollment Total Other 7813 Total

9 Broadest range of new drugs and trials available in the West Draw patients from across 10+ state area Phase I studies open at any given time Catchment Area: Denver Metro Area Colorado 9 surrounding States Enrollment: /year pts/year pts/year

10 Inhibit specific target(s) in cancer cells Relative sparing of normal tissues Low response rates in all tumor types without selection Potential for marked activity in tumors with the target

11 Growth Factor Receptor Tumor Cell Mutation causing overdrive signaling Growth Nucleus

12 Growth Factor Receptor Immune System Growth Tumor Cell Tumor Microenvironment Metalloproteinase Inhibitors Vaccines Anti-CTLA4 (melanoma) Nucleus Blood Vessels Bevacizumab Sunitinib

13 Tarceva (erlotinib) EML4-ALK Translocation (ALK +) 3-7% all NSCLC 10-20% adenocarcinoma, never or light smokers Ladanyi et al.

14 PF Overall Response Rate 64% (crizotinib) Phase I Dose Escalation All Tumor Types Expanded Cohort Disease Control Rate 90% ALK+ NSCLC Other tumor types with target Expression r. Ross Camidge la Hegland bs4denver.com Bang et al. ASCO 2010

15 Apoptosis/Cell Cycle Arrest Kinases (Flt-3, c-kit, CSF1R) ENMD 2076 Angiogenic Kinases Aurora Kinases (Aurora A ) (VEGFR2, VEGFR3, bfgfr)

16 Prophase Metaphase Anaphase Aurora A Aurora B Adapted from Keen et al. Nature Reviews Cancer 4:

17 Patients active on study Patients off study Patient(s) with PR by RECIST *Indicates patients with confirmed partial response by CA-125 Number of days indicates number of days on treatment to date or at time of study termination Data current through 21 October 2009 CA-125 is a valid marker of benefit

18 CMET (cmet mutation or ALK+ NSCLC) MEK (BRAF+ melanoma) MDM2 (p53 wt sarcoma) PI 3K IAP Ab TWEAK (tumor necrosis factor like weak inducer of apoptosis) Ab PAK4(p21 activated kinase ) EGFR/HER3 Hsp90 (Her2+ br ca) Hedgehog signaling pathway (BCC, Patched 1 mutation) Neuropilin 1 (NRP 1) (coreceptor for VEGF) DLL4 (delta like ligand 4), Notch pathway, angiogenesis Polo like kinase IGF1 R JAK2

19 FLOW IN: a) Patients with few standard therapy options/tumor specific trials left b) Patients who do not wish chemotherapy standards at present/ever c) Patients considered GU for access to specific experimental drugs with strong promise for their tumor type Breast Other Phase I Lung GI Head/Neck UCCC Hub and Spoke Concept Lung GI Head/Neck Ped/Sarcoma Melanoma Hem Breast GU Other Heme Peds/ Sarcoma Melanoma

20 Other Lung UCCC Hub and Spoke Concept GU GI Lung GI Head/Neck Breast Phase I Head/Neck Ped/Sarcoma Melanoma Hem Breast GU Other LOW OUT to tumor-type pecific oncologist/primary ncologist: ) Patients - to get any remaining standard drugs ) Patients - to get tumor type specific later phase clinical studies ) Drugs - to enter specific tumor types phase II or III trials Heme Melanoma Peds/ Sarcoma

21 BAD Not everyone qualifies Difficult to access Unknown side effects Unknown efficacy Unknown long term risks Concern over costs to patient Long term availability not guaranteed More visits, more attention GOOD Many new drugs have fewer side effects that traditional agents New drugs can work very well for some people chance at something new Traditional cross resistance mechanisms may apply less to newer targeted agents More visits, more attention

22 Relationship and communication (prize poodle) fewer patients = more time per patient specialized research team coordinating care Documentation and reporting (test pilot) Option to withdraw consent at any time Trials teams try to be flexible, however, trial design is relatively fixed role in quality of life: No offense, but if this IS the end of my life, I d like to spend as little of it with you guys as possible

23

24 CCC Medical Oncology: reast Cancer/Sarcoma astrointestinal Cancer enitourinary Cancer ynecological Cancer ead and Neck Cancer ematological Malignancies ung Cancer kin Cancer Developmental Therapeutics Team (Phase I Team) General and GI Gail Eckhardt, Wells Messersmith, Steve Leong, Colin Weekes General and Thoracic Ross Camidge General and Pediatric, Sarcoma Lia Gore General and Genitourinary Elaine Lam General and Melanoma Karl Lewis General and Head and Neck Antonio Jimeno, Madeleine Kane Phase I Lung GI Head/Neck Ped/Sarcoma Melanoma Hem Breast General and Breast Jennifer Diamond