Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Clinical Trials in Colon Cancer – the promise for better outcomes Mital Patel MD Gastrointestinal Medical Oncologist November 12, 2016 Primer on Clinical Trials Definition, types, advantages and challenges 2 What are Cancer Clinical Trials? The NIH Definition: “A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.” The common (old) definition: Clinical trials are research studies that involve volunteers used to advance science. Many clinical trials study new cancer treatments. The current definition: (especially for phase III trials) (Treatment) Clinical trials are treatment options which are delivered in a research setting (and hence monitored rigorously) which have the potential to benefit the patient, provide early access to groundbreaking therapies, improve quality of life and…advance science. 3 Phases of Trials Years 3-6mo upto 2 yrs 1-4yrs Preclinical Animal studies Cell Lines Phase I All tumors Safety Dose finding Administration Maybe efficacy Phase II Efficacy More safety data Phase III Randomized Is it better than standard? Is this difference real? Side effects Phase IV Effects in the real world Long term side effects Danger signals 4 Phases of Trials: efforts to accelerate Years 3-6mo upto 2 yrs 1-4yrs years Preclinical Animal studies Cell Lines Phase I All tumors Phase II Phase III Safety Cancer specific Dose finding Efficacy Administration Randomized More safety data Is it better than standard? Maybe efficacy Cohort expansion Randomized Phase IV Effects in the real world Is this difference Long term side Larger numbers real? effects Side effects Danger signals 5 Types of Cancer Clinical Trials • Cancer Prevention trials • Screening trials • Diagnosis trials • Cancer Treatment trials • Quality of life trials • Comparative effectiveness / Cost effectiveness • GENOMIC trials 6 Genomically oriented trials (Not genetic) BASKET TRIALS UMBRELLA TRIALS 7 Benefits of participating in cancer clinical trials Direct • Potentially better treatment • Access to new medications • Improvement in quality of life Indirect • Regulatory necessity • Advancing science • Benefit to other patients • The value proposition 8 Advantages: potentially better treatment Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomized phase 3 trial 9 Advantages: Access to newer treatments • Recruitment of patients :April, 2009 to February, 2012 • Recruitment of patients from October 2008 to February 2012 • Phase 1 study published in June 2012 in the same edition • Phase 1 study published in June 2012 in the same edition • Then phase II, then phase III • Then phase II, then phase III • FDA approval (Keytruda) • FDA approval (Opdivo) – Melanoma: 2014 – Melanoma: 2014 – Lung: 2015 – Kidney and Lung: 2015 10 Advantages: improvement in quality of life • TAS-102 vs placebo • It slowed down the decline in causing weakness and debility 11 Advantages: Regulatory • Phase III trials compare treatments to standard of care. • For new drugs to be approved by U.S. Food and Drug Administration • They also must be done before new surgical or radiation therapy methods are regularly included with cancer treatment. • Participation in clinical trials – better survival. • They remain Category 1 recommendation for most national cancer guidelines. FDA approved drugs in colorectal cancers Chemotherapy Antibodies Oral targeted molecules 5- Fluorouracil Panitumumab (Vectibix) Regorafenib (Stivarga) Irinotecan (Camptosar) Cetuximab (Erbitux) Oxaliplatin (Eloxatin) Capecitabine (Xeloda) Bevacizumab (Avastin) Lonsurf (TAS102) Ziv-Aflibercept (Zaltrap) Ramucirumab (Cyramza) 13 Strong network Organizational • ASCO: • AACR • National organizations: – Colon Cancer Alliance – American Cancer Society 14 National priority 15 But its not all good….. 16 Low participation in oncology clinical trials • California Cancer Registry 2001-2008 – < 1% – Al-Refaie et al. Annals Surgery 2011 • NCI-Sponsored Coop Group Trials Enrollment 1996-2002 – 1.7% of incident cancer cases enrolled – Lower in racial/ethnic minorities, older patients – Murthy et al. JAMA 2004 • NCI Comprehensive Cancer Centers 2013 – 12% median – http://cancercenters.cancer.gov/DT/DT3 Key influences in participation in clinical trials Patient Physician 18 Key influences in participation in clinical trials Patient Families Physician 19 Key influences in participation in clinical trials Patient Healthcare Physician systems Families 20 Key influences in participation in clinical trials Patient Insurance Healthcare Systems Physician Families 21 22 Key Barriers: Physician Lack of knowledge of available options Time needed to enroll on trial Lack of motivation Clinical equipoise Lack of resources / research personnel /Cost of trials 23 Key Barriers: Patient wishes Side effects of the experimental drug Lack of effect, Is this actually the best option for me Financial / Logistics /costs /Travel / Health Insurance wont pay Sugar Pill / Placebo Randomization/ Loss of autonomy 24 Background: effects of low accrual to CT • The success of a clinical trial is dependent upon accrual within a specified time frame • Low accrual leads to – Inadequate statistical analysis of outcomes – Premature trial closure – Increased costs – Ethically unfair to the patients who enrolled in the trials Myth 1: I will be a guinea pig Depends on the definition of Guinea pig – Several committees and agencies watch over patient safety before, during, and after a clinical trial. – Most regulated : Institutional Review Board • Includes doctors, statisticians, community advocates, clergy, lawyers, patient advocates • Mandated by federal law: – Risk – benefit ratio – Informed consent, option to withdraw – Data Safety Monitoring Board Myth 2: I will get a sugar pill (placebo): Not necessary S1406: Randomized Phase II Study of Irinotecan and Cetuximab with or without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer Patients with BRAF positive CRC Irinotecan and cetuximab Irinotecan and cetuximab and vemurafenib 27 Myth 3: I will get a sugar pill (placebo): yes 28 Some key things to remember….. • Statistical significance and clinical significance • A similar setting, a similar population, similar disease stage…. But still it does not account for individual differences – Inclusion criteria help make sure that people in a clinical trial are medically similar – Exclusion criteria help keep people safe. Targeting Efforts to Ensure Access and Optimize Decisions About Clinical Trials • Use the internet • Seek Patient advocates • Seek support groups • ASK your oncologist Patients Healthcare teams • Train all staff • Invest in trial infrastructure Physicians • Informed consent • Cultural sensitivity • Understand patients point of view • Invest in trial resources: easy matching 31 32 • http://www.cancer.net/navigating-cancer-care/how-cancertreated/clinical-trials/pre-act/play-oneall/what_is_randomization • http://www.cancer.net/navigating-cancer-care/how-cancertreated/clinical-trials/pre-act/play-oneall/who_pays_cost_clinical_trial • http://www.cancer.net/navigating-cancer-care/how-cancertreated/clinical-trials/pre-act/play-oneall/what_pharmaceutical_drug_companies_gain 33 Starting points for Information on cancer clinical trials • Cancer.net including the PREACT videos • Cancer.gov (NCI Clinical trials.gov) with database • American Cancer Society: Free phone searches • Website of your local Academic Oncology Centers • Calls to your community oncology centers • Colon Cancer Alliance • Webchats, blogs, Youtube, Twitter (with a grain of salt..not your first stop !) 34 Advances in Colorectal cancer Latest results, the buzz….whats in the pipeline 35 Updates from recent key clinical trials in colon cancer • 18 months • Major national / international meetings – ASCO, ESMO, AACR, GI ASCO • By intervention group – Prevention, Diagnosis, Treatment advances, Supportive care 36 Practice changing / Key observations • Screening guidelines • Prevention strategy • Detection of recurrence • Right vs Left • Immunotherapy 37 1. Prevention (Why are we talking about this?) • Adults aged 50 to 59 years with a ≥10% 10-year CVD risk, USPSTF recommends initiating low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer (CRC). 38 2. Screening: which test? • Colon cancer screening in patients 50-75yrs of age – but can use ANY test – Stool based tests like guaic testing, stool DNA testig – Direct visualization like colonoscopies, sigmoidoscopies 39 3. Surveillance: How much is needed? POST SURGICAL FOLLOWUP INTENSIVE SYMPTOMATIC SCREENING F/UP CEA CEA + CT scans CT scans Visits +/- single baseline CT 40 Testing is important in colon cancer POST SURGICAL FOLLOWUP INTENSIVE SYMPTOMATIC SCREENING F/UP CEA CEA + CT scans CT scans Maybe not in rectal cancer Visits +/- single baseline CT 41 4. Side matters! 42 4. Right vs Left 43 44 45 Retrospective analysis • Right colon (Median overall survival) • Left colon • 19.4 months • 33.3 months • With cetuximab: 16.7 mo • With cetuximab: 36mo • With Bevacizumab: 24.2 mo • With Bevacizumab: 31.4mo 46 5. Is ‘more the merrier’ or is ‘four a crowd’ ? • Slowed down progression • Had better responses • Had more side-effects • Improved survival CHARTA Phase 2 trial 6 mo induction maintenance • • • • Positive study Slowed progression Improved response rate More side-effects / Dose decr 47 6. Immunotherapy in Colon cancer please! Checkpoint inhibitors, how they work? Immune system contacts the cancer cells 48 Immunotherapy: Checkpoint inhibitors, how they work. Immune system contacts the cancer cells The immune system brakes 49 Immunotherapy: Checkpoint inhibitors, how they work. Immune system contacts the cancer cells The immune system brakes The brakes are released, Immune system attacks cancer 50 Immunotherapy in colon cancers 51 52 53 Newer approaches to immunotherapy • Cobimetinib + Atezolizumab in KRAS-Mutant mCRC – 17% ORR, 72% 6-mo OS higher than rates observed for individual agents or standard of care – Current phase Ib study accumulating more mCRC pts – Phase III trial also recruiting mCRC pts to evaluate this combination therapy 54 7. A look at the future. • Stem cells are important in self renewal of cancer cells – Recurrence – Metastases – Resistance 8. Genomics Mismatch repair Kras Extended Kras and Nras BRAF POLE 56 SUMMARY Aspirin for primary prevention -50-59yrs, at least 10 yrs Screening for colon cancer is key….which test may not be ! Surveillance may be tailored for colon / rectal cancer Different antibodies for different sides.. Ready for prime-time? 4 drug regimen for response in selected patients Immunotherapy in the works – compelling evidence for MSI-H tumors Stem cell inhibitors, POLE mutations, BRAF inhibitors in the pipeline 57 Thank You