Anaplastic Thyroid Cancer

good evening. thank you for attending our nowfourth seminar of this woman's cancer quarterly series. i'm honored to introducemyself, first of all. i am the director of thedivision of gynecologic oncology here at stanford. i joined stanfordabout two years ago. and it's been reallya great journey so far

and a terrific groupof people to work with. i'm particularly proud of ouractivities in clinical trials for gynecologic cancers,as it's so well supported by the clinical research group. we have sharamya andashley, and bela here that really responsible forthe main part of this work. and what i want todo today is i want to tell you a little bit aboutclinical trials in general. i want to tell you what it meansto conduct a clinical trial,

what the phases of those, andwhat you can benefit from, and potentiallywhat the risks are. in a second section,i want to show you how to find clinical trialsat stanford and beyond, and particularly how we doit, we at the stanford cancer institute, and websites for thenational institutes of health. and then the thirdsection we'll focus on what i think arepromising new treatment strategies for ourgynecologic cancers,

in particular how we targetspecific cancer growth pathways, how weuse parp inhibitors, and how we are very excitedabout new developments in immunotherapy. what is a clinical trial? there are a lot ofdifferent definitions. this one is one that i thinkdoes fit very well, in general. it is research toprospectively, so going forward, assigns human subjectsto intervention

and concurrentcomparison control groups to study the cause andeffect relationship between a medicalintervention, like a drug, and to health outcome. that really issomething very general that we can apply for clinicaltrials in all diseases, but also fits very wellfor cancer disease. why do we need todo clinical trials? why can't we just take a drugthat has shown great efficacy,

and great promise in ouranima models and cell lines in the laboratory, andgive it to patients? well, clinicaltrials are actually meant to provide a scientificand systematic approach of research in human subjectsthat can be carried out very efficiently,ethically, and it's supposed to optimize safetyas well as a potential benefit for the patient. we also have to make surethat the conclusions we

reach from these trialsdo reach a statistically meaningful result. without that, we can't reallyrecommend our treatments to patients withgood consciousness. there's different typesof clinical trials. there are prevention trials. we have given aspirin topatients in an attempt to prevent certain cancers. there are screening andearly detection trials.

and some of youmight have been part of screening trialsfor ovarian cancers, where we use ultrasound,the cn25 tumor marker, and pelvicexams on a regular basis to detect those cancersearly on, none of which have shown to really changethe outcome of ovarian cancer patients, unfortunately. yes, those trials thatevaluate diagnostic procedures. we some trials at stanford anda very active group in radiology

that investigates newpet scanning modalities. we are part of at least acouple of these studies. in addition andparticularly nowadays, there's a lot of emphasis ontrials that look at quality of life and supportive care. it's very importantat some point in the treatment ofevery cancer patient to look at whether theinterventions that we have at our disposition do weimprove the quality of life,

and how they impactthe overall lifestyle. but i think what most of youare interested in is treatment trials. those are trials thatinvestigate new drugs, or investigate drugsthat are already approved in a different combination. and those trialsare supposed to make a difference for the patient. clinical trial protocols area very, very important part

of clinical trial. what is a clinicaltrial protocol? it's really a written detailedaction plan that's sometimes goes up 150, 200 written pages. and i know my clinical researchgroup knows these very well. we read them in all details. and what it does is itdoes provide a background and rationale of these trials. why is it important, andwhy does it make sense

to use a certain drug? it also describes thetrial objectives and goals. every trial has adifferent endpoint or goal. some trials are justlooking for safety. does a patienttolerate this drug? some other trials look foris this drug really effective against the cancer. the clinical trialprotocol outlines in great detail everythingyou need to know

to execute the trial correctly. that's the sequenceof events, the design, and the requirementsfor enrollment. and those if you who havelooked at clinical trials know very well that they'revery specific inclusion and exclusion criteriafor each trial you might be a candidate for. very important inthis clinic protocol is an in depth descriptionof safety and stopping rules.

we need to know at whatpoint the drug becomes too toxic in order to continuethe patient on the trial. we also need toknow at what point to stop the patient in the trialwhen the disease progresses. that again all is includedin a clinical trial protocol. it does include a verydetailed statistic plan. and we always have statisticiansthat look at the numbers because it has to bestatistically meaningful at the end of the trial,as i mentioned before.

we as investigators, with thehelp of our clinical research coordinators, have to followthis clinical protocol was very, very strictly. and if there'sany deviations, we have to report thosedeviations immediately. as i said, there are differentphases of clinical trial. the most important phasesare phase 1, 2, and 3. what is a phase 1 trial? a phase 1 trial is when a drugor intervention is first ever

administered to human beings. and it mainly is supposed toassess the safety of the drug, not so much the efficacy. now you might get aneffect of this new drug, but that is really asecondary endpoint. again, it is moreimportant to know what dose the patient tolerates. we usually start thesetrials at a low dose, and then slowlyincrease the dose

to find the what we callmaximum tolerated dose. and in some cases, calledthe optimum biological dose. the groups are small. they're 20 to 25 patients first. and if it's safe, we escalatethis to more patience. and it can go up to50 to 80 patients. there is no blinding,meaning you know you're going to get the drug. it takes less than otherclinical trials-- about three

to six months to accomplish. and the success rate of thephase 1 trials in general is about 70%. what that means is 70% ofthe drugs that we are testing are considered to be safeand rather well-tolerated by the patient. now if the phase1 study does not show any unacceptabletoxicity, we move on to theseso-called phase 2 trials.

and those trials are nowfocused on again the safety, but much on the effect ofthis drug on this disease. they often arecontrolled trials, so patients receivingthe drug and then they're compared with a very similarpatients that received a different drug treatment. and that's eithera placebo, or it's a drug that's alreadyestablished in this situation. the trials are larger.

they're 200 to 500 patients. so you have moreopportunity to participate, and therefore theytake more time-- about six months to two years. the success rate is about 35%,meaning that about a third of all these trials,the drug indeed shows some superiorefficacy compared to the standardtreatment and placebo. now, when that is thecase, you usually then

see this as [inaudible],but it should move onto a phase 3 trial. and those are that trialsthat are really large. they have up to 1,000 patients,sometimes even more in them. they are done as multi-center,sometimes international trials. they usually double blind it. that means thephysician doesn't know, and you don't knoweither whether you get the drug or not.

we randomize patients. so we pull the number ofthe hat and then allocate either placebo, control drug,or the investigational drug to you. we're very careful aboutrecording all adverse side effects, and of course,do a very detailed statistical evaluationof all the clinical data. those are long trials. they take up to fiveyears to accomplish.

and the overall success rate isthen quoted as being about 25%. so not all the developmentthat's expensive development leads to approval ofa drug by the fda. but ultimately, allthese trials are done to make a newdrug or intervention available to patientsfor this disease group, and approved by the fda. so in summary, we have threemain phases of clinical trial. and i want you tobe aware of this.

there's a small number thatare involved in phase 1, which mainly looks at safety. we have severalhundreds of patience that are involvedin phase 2 trials. and more and morethose are done. and then in phase 3, the largetrials, the longer trials that look really at,again, safety, dosage, and effectiveness. there is a so calledphase 4 trial.

those are trialsthat are usually done after the drug isapproved, after marketing. and those trials look atvery specific sub-groups are for a veryspecific side effects. but it's notnecessarily something that you as a patient in theprocess of gynecologic cancer treatment might necessarilywould be facing. so when you select trials,look very carefully at what phase this trial is in.

now what do you benefitfrom by participating in clinical trials. well first of all, you getvery, very early access to new treatments, particularlyin the phase 1 and 2 trials. and that means youcan potentially be one of the first patientsthat benefits from a new drug. of course, there's never aguarantee, as i showed you. but that could very well happen. you also will experience thatwe will closely follow up

with you, and much closerthan you see in the regular follow up on a standard therapy. the protocols really demandus to have more frequent blood tests, more frequent imagingstudies, more frequent visits with your physician and witha clinical trial coordinators. and after our participationin any trial, diagnostic, screening, or treatmenttrial, we ultimately advance medical knowledge,even if the trial at the end does not turn outwhat it might of

promised at the being,meaning being negative. there are also risksof clinical trials. you can have unexpectedside effects. and that can happen inany phase of these trials, even if you think a drug iswell tolerated in phase 1, enrolling more patientsin phase 2 and 3 might show you side effects thatyou didn't see and anticipate before. also you have to consider thatnew treatments are not always

better. they might sound good, andthey might be based on a better biological rationale. but they might not showthe clinical efficacy that we all want. and if we drug works forone person, or one patient, it might not work for everybody. consider also the additionalcost some of them for you might as a patient relateto traveling to our sites

where we do these trials,particularly patients that come from remote area. for those patients, it might bea significant additional cost that is not necessarilycovered by the trials or by the insurance company. there are patientsthat don't necessarily want to participatein clinical trials. there are physiciansthat don't think that patients should participatein clinical trials yet.

it's very importantas an adult to think about this proactively. we think thatphysicians oftentimes lack knowledge ofappropriate trials. and that's somethingthat i think transcends to all physicians' areas. it is difficult to know thealways changing landscape of different clinicaltrials and approaches. and i'll show you in a fewslides what i mean by this.

you have to consider thatthe clinical trial requires a lot of support staffand physician involvement. we have a luxuryreally at stanford to be extremely well supported,but this is not necessarily the case in a peripheralcenter of care. some physicians donot want to give up control of the patient'scare because it is much about therelationship between physician and the patient that guidestheir recommendations.

and some physiciansare even a little concerned about how a patientmight react to their suggestion to go in a clinical trial,meaning that might put them in a place where they haveless hope for better outcome. on the patient'sside, there's also lack of knowledgeof clinical trials. and we are working veryhard on improving this. there's lack of accessto clinical trials. if you live outremotely from stanford

and it takes youhours to get here, it's difficult to firstknow about trials, and then second,to get to the site where you can havethose conducted. some patients actuallyprefer for physicians to make the treatment choices. they have a good physicianpatient relationship, and they feel liketheir physician knows what is the best for them.

some patients aresuspicious of research, don't want to be usedas research objects. and that's, again, somethingwe're really trying to change. our trials arevery well watched, and safety is our one priority. some patients, as i said, havelogistical and person obstacles to participate inclinical trials. and again, something that we'reworking hard on improving. now what does it meanto open a cancer study?

and i'm going to showyou on the next slide a flow chart, which will beextremely detailed and complex. it'd be easy to takea drug where we think it works great in animals. so why not put thisin human beings, and write the prescriptionjust like every other drug? well, you can't dothis in clinical trials because you have to go througha number of regulatory approval processes.

and this is a flowchart that i think is very, very impressive, wellput together by the stanford cancer institute. and a lot of these processeshave to be in place in order to get a drug to the patient. it can take a while. and that's why some of you mighthave experienced frustration waiting for a study to open. and that's the reason why.

now we are, i think,involved in most trials we have to involve what'scalled the irb and the src at stanford. this is shown in thegray box, which i'm going to focus on right now. it's called theinstitutional review boards and the scientificresearch committee. those are really the twovery important local boards and committees that needto look at the trial.

so what does the irb do? the irb is a committee, thoseare physicians, scientists, statisticians, evenlaypeople, that is formally designated to approve,monitor, and review research involving humans. and they're primaryconcern is they're sure that the patient doesn'texperience any physical or psychological harm. so the safety of patientsis very, very important

to this committee. it also makes sure thatpatients are fully informed and can voluntarily participatein this clinical trial. there's absolutely noobligation for any patient to consent to a trialunless they're completely informed about this. and we do this, i think,extremely well at stanford, that we go into all greatdetails in informing patients about the risks and benefits,the rationale of our trials.

scientific review committee, thesrc, is yet another committee-- different personnel. and this committee primarilyfocuses on a scientific review, the scientific merit. is it feasible to do thisstudy here at stanford or in the environment,and how are cancer center resources utilized? you have to considerthat every trial needs a certain number of tests.

can we do these testshere at stanford? can we provide theimaging studies? and does this study actuallymakes scientific sense? please. is the scientific reviewcommittee specific to oncology? they do review mostly cancertrials, that's correct. the irb, they reviewbasically our trials that have to do with cancerhere because we are a national cancer institute designated bythe nci, the national cancer

institute. so it's a requirement hereat stanford to have that. irb-- there's medical irbsthat review all other trials, including cancer trials. now what does a clinicalresearch coordinator do? i mentioned this before. those really are thepeople that do our work. and they're involved from studyconception, here on left side. they monitor all studyactivities, from consent form,

to screening, tofinding patients. they're managers thatfacilitate the study contact. they document very carefully. and a lot of time goesinto documentation nowadays of side effects,doses given, and timing. they're also involved inthe regulatory processes, with not only theirb and the src, but also the fdaif that's required. and then last butnot least, they

have to be concerned aboutthe finances of each trial. trials are very expensive. and we get supportby the companies that want to develop the drugs. we get support by thenational institutes of health, and the nationalcancer institute. we have some investigated[inaudible] trials that are supported by grants andalso supported by the stanford we do philanthropy evento support our trial.

so the resources comereally out all directions. but it has to fit financially. we have very special feesfor research related studies. so they're not chargedat the same level as the insurance companiesare being charged for a proof procedures, andnon-research activities, or standard treatment. but still doing abudget for these trials is extremely importantand necessary.

so here's our clinicalresearch group. again, we have ashley powellwho leads this cr, bela shah, sharamya ram, susanfriedrich, who does a lot of our cooperativegroup study of groups in the united states likethe gynecologic oncology group, that organizes onlyclinical trials in oncology. and then alma gonzalez justjoined us more recently. alma is going to beprimarily responsible for investigatedinitiative trial,

meaning that if i havea good idea for trial, it's approvedthrough the network of regulatoryprocesses, alma will be responsible forthese type of trials. if you have any questions,here's a phone number. please use this and call usfor any detailed information. so how do you find clinicaltrials at stanford and beyond? and i do know for the fact thati have multiple conversations every week with patientson that particular topic.

it's not easy. it's not easy for usphysicians either, but i'll show you acouple of resources that i think are veryrather easy to navigate, and very, very resourceful. the first one is our websitefrom the cancer institute. this is what it looks like whenyou go to cancer.stanford.edu. this here is, as youprobably know, the entrance to the cancer treatment centerwith the fountain in front.

it has the right in themiddle an option to look for clinical trials. so let me click onthe clinical trials. and i find a site that lookslike this, find cancer clinical trials. and those are allthe clinical trials that are going on atstanford at any given time. you can look by keyword,you can look by condition, you can look by drug use.

you can also look by what'scalled the eligibility flowchart, shown hereon the right side, which allows you to enter morespecifics about your condition. for example, have youhad chemotherapy before, what is your condition,what is your disease? is it ovarian cancer,cervical cancer? what kind of chemotherapydid you have before? and if you putthese parameters in, it will more specificallylook for a clinical trial.

now let's say ilook for trials that enroll ovarian cancer patients. i type this keyword in here. i look for trials thatare accepting patients. some of the trialsthat are registered might not be openyet, or might not be recruiting patients anymore. but the ones that are acceptingpatients are six of them. and this is shown now on thenext segment i click in this.

and as you go throughthese studies, you see the title of them. now the first studythat comes up here and that i know how to readfrom the very end of the room is a maintenance study withniraparib, a parp inhibitor, compared to placebo and patientswith platinum-sensitive ovarian cancer. so i now know it's anovarian cancer study. i know it's forplatinum-sensitive patients,

and i know it's aplacebo controlled trial where the drug to bestudied is a parp inhibitor. now when you clickon that title, it goes to the next website. and that's probably easier toread from the end of the room. but here is a much moredetailed description, and you can read this. so i know now those are patientsthat have brca mutations, or tumors with high-gradeserous histology.

and if you happen toknow this information, you know, as a patient, i mightbe a candidate for the trial, if i'm interested in it. again, if you havequestions, there's always a primary contact, inthis case ashley powell again. and if you pick up thephone, call the number, you can discuss this trialwith her on the phone. there's is more on this website. as you scrollfurther down, you're

getting down to the inclusioncriteria and extrusion criteria-- something youmight want to read at home. it shows, again, that youhave to have either a high grade serous ovarian cancer,or have a brca mutation. you'll also find out that youcannot have had invasive cancer other than ovarian cancer withintwo years prior to enrollment of the trial. so there's someexclusion criteria that you might want to look at.

now this is often reallywritten in very medical terms, but again for any questionsit's a quick phone call. and we can clarifyanything you want to know. now don't forget that allgynecologic malignancies are so called solid tumors, that'scompared to leukemias that are more blood tumors. solid tumors can also besubsumized as clinical trials. and if you look for solidtumors on the stanford website, you find 30 trials.

and each one of those trials youcould be a potential candidate for. it might be a trial forgynecologic cancer primarily. but since it's for solidtumors, the investigators of these trials might bevery open to consider you as a candidate for the trials. now here i pulledup one of them. this is a study that is done bydr. ron levy who is certainly one of the most accomplishedinvestigators at stanford.

he's the one whodeveloped a toximap. here he uses a drugthat's called urelumab. it's an immunotherapydrug that's stimulates the immune system. and as i boxed here,it does enroll subjects with advanced and/ormetastatic solid tumors, which gynecologic malignancies are. so if you happen to not finda trial for ovarian cancer that fits you, lookfor these trials.

they're usually phase 1 trials,sometimes phase 2 trials. they're trying to finda target for this drug, or a disease for this drug. but this drug has some efficacy. that's why they're enrollingall solid tumor models. so don't forget aboutlooking for solid tumor as your key word. i'm also introducing now thestanford cancer institute clinical trial application.

there's an app thatyou can download easily on your smartphone. this is what the iconis going to look like. sci clinical trials. it's really easy to navigate. it's just likethe website i just showed you, a way ofsearching for clinical trials. you can do this by conditions. we'll get you to theclinical research coordinator

that you may call foradditional information. please use this. and please use it if you're apatient interested in clinical. often clinical trialsare subject to change. we open and close themvery, very quickly. and i think that looking atthe site on a regular basis, about once a month, mightmake some sense for you. so this is a really easy wayto do all this on your iphone or ipad.

we also have people in thecenter of clinical trials office that give you informationreferral like ellen dinucci, who is here in theaudience, who is really a fabulous clinical trialsrecruitment specialist. and if you call ellen, she willguide you to clinical trials and provide you informationabout any related resources. i think you shouldtake advantage of this for any trials. this is not onlygynecologic cancer trials,

but for any cancer trialsgoing on at the stanford cancer we have also a spanishspeaking person for anybody who prefers tocommunicate in spanish. this is adriana morieko. she really makes sure that ourtrials are diverse, and offers these services to ourspanish speaking population. we do have asianinterpreters, as you probably know from our clinics. they can facilitatetranslation of our conversation

with the patientabout clinical trials. i don't think we haveanybody right now dedicated in the stanford cancerinstitute for that purpose. ellen, correct me if i'm wrong. no, i think we haveto [inaudible]. but we have this available. so don't feel likeyou're left out if you speak a different language. we will make sure you get theinformation that you need.

now another website thati find extremely useful is this one, clinicaltrials.gov. it's actually a serviceof the us national institute of health. and that's a very, verycomprehensive website. and if you can readthis from there, they right now have183,000 studies listed. not all of them are recruiting. it's not all cancer.

and it's not all goingon the united states. but a significantproportion of those studies are in cancer, are recruiting,and done very close to our home. you can use this studyand this website, as well. and as we look forovarian cancer recruiting studies, all studiesthat are interventional, it will pull up a verysimilar list of studies where i find 458ovarian cancer studies

all around the world that arecurrently recruiting patients. and i didn't do this onpurpose, but the same study that we had just opened onthe stanford cancer institute website. the niraparib parpinhibitor study shows up here as a first study. you can click onthis title here, and very similar towhat we provide here at the stanfordwebsite, it will pull up

very detailed information. read that detailed information. it goes furtherdown in the website. it gives you contacts. it also gives you centerswhere these trials are done. the centers might becloser to where you might want to go as a patient. it might not benecessary stanford, but other institutionscloser to home.

you might alsoconsider this website as a resource for othertrials that are not even done at the [inaudible]. but i thinkpreferentially you want to stay close to home tofacilitate and make it easy for you to followall trial procedures. and that's what iwant to show you here. this website willgive you the option to look for trialsthat are very specific.

if you want to look fortrial in california, it allows you to do this here. in this case, i looked forovarian cancer recruiting trials phase 3, so largestudies, only in california. and i find a totalof nine trials here. again, for some reasonwe get the same trial at the very top,niraparib, and others that you might be interested in. of course, you're welcometo travel to other sites.

but i think given theinvolvement in clinical trials requires a lot offollow up, it might be impractical to travelto far of a distance. so this was finding clinicaltrials at stanford and beyond. and i hope you use this resourceif you need this as a patient. we are happy to talk toyou about clinical trials that you find on these websites,and you find interesting. because a lot of the decisionmaking process really depends on what yourphysician, or we

as a group ofgynecological oncologist think about thesetype of approaches. not every trial we thinkhas a lot of validity. but a lot of them, ithink, do have the value. and i'll show you now inthe last section of my talk what i think are some ofthese promising new treatment strategies for our patients. now i'm going to talk abouttargeting specific cancer growth pathway parpinhibitors, immunotherapy,

there's of courseother strategies you could talk about. but i think in theinterest of time, i will focus on thesethree different areas. so let's start with talkingspecific cancer growth pathways. we know a lot more about thebiology of cancer than ever before nowadays. there are giant databasesall around the world,

including from stanfordthat have elucidated a lot of the molecularstructures, pathways, ways that cancer cellsare using to grow. so we went from just takinga tumor out from a patient. they could put this underthe light microscope and tell you, well, this isa cancer from the cervix, or the uterus, or the ovary. they can do a verysophisticated study, including electron microscopy, whichwe're not using clinically,

down to molecular analysis. we can look at gene mutation,we can look at protein. and we can get muchmore sophisticated. and it turns out to be avery complex network of genes and proteins that is extremelyimportant for the cancer cells to grow. a cancer cell looksvery different compared to normal cell. the big challenge nowadays iswhich one of these many pathway

is really importantto the cancer cell. which switch do i have toturn off to kill this cell. and here we, i think,have made some progress. and i'll show you what areasi think might be promising. cancers have a lot ofdifferent mutations. and here's a studythat was published about a couple of yearsago by bert vogelstein who looked at all kindsof different cancers. and he basically askedhow many mutations

do you actually find in thedna of these different cancers. and this chart on theleft side shows you that every cancer has adifferent number of mutations. and it ranges anywherefrom only four in this very rarerhabdoid childhood cancer. lung cancer has a lot of 163and some colorectal cancer, even more than that. ovarian cancer, at this point,was kind of in the middle. but as the daysand weeks go by, we

do actually find moreand more mutation. the problem for usis which ones are the really important mutations. which ones are the mutationsthat they should design drugs for? and you pick your choices here. but we have i thinkidentified a few. and i'll show you some veryimportant mutations here. this is a different way oflooking at ovarian cancer.

we use to, and still do,look under the microscope and say, well, thisis an ovarian cancer of the epithelial subtype. it's either high gradeserous or low grade. it's a mucinous, clear cellor an endometrioid cancer. and some of themare not epithelial. they're called sex cord stromatumors or germ cells tumors. now i want to directyour attention to the genes that aremost frequently mutated

in these histological subgroups. and want you to recognizethat these genes are a little different. when you look at the highgrade serous ovarian cancer, this tp53, a very importanttumor suppressor gene is mutated in thevast majority of them. and so are thebrca 1 and 2 genes. they're most frequently mutatedin this histological subtype. other cancers like lowgrade have mutations

in very different genes. listed here are[? brav, ?] kras, nras, and [? erptwo. ?] and yet clearcell carcinomas and endometrial carcinomas have mutations veryfrequently in what we call the pr3kinase pathway. so you start seeingcertain subgroup of cancers that wedon't divide anymore by histological subtype, orwhat the pathologist thinks is the epithelialsubtype, but rather

by the mutation spectrum. and that is exactlythe information that we want to use todesign new targeted therapy. here's what they call thestanford molecular profiling. it's just came out. and that's a mutation panelof right now 198 genes. we have wrote thisout in lung cancer. we are starting to do thisin gynecologic cancers. i do know that a lot ofother companies as foundation

medicine, or foundation1 and clarity foundation will provide you with thatvery same information. but it's important for usto get this information from your tumors, particularlyat some point of the treatment where we're looking fordifferent treatment choices. there's a lot of genes here. and we get a lot ofinformation out of this. we don't know exactly how touse this information absolutely corrected these days,but we know some.

here for example is what wecall the pi3kinase pathway. and i don't want to take youthrough the entire biology here. but in essence, ifyou follow my cursor, you have a cell membrane here. these cells, the cancercells, get activated at the cell membrane level. and then an enzymecascade, so to speak, does signal into the cell viaa number of different proteins.

and that signaling cascadeultimately at the very bottom leads to increased growth ofthe cells, increase metastasis, increased metabolism. so you make the cellmore aggressive. now since we know about a lotof these different proteins in this pathway,we can design drugs that block these proteins. because if we switchthis pathway off, the cells are deprived of avery important growth pathway.

and we can do this nowadayswith certain drugs. we have a clinical trial hereand gynecologic malignancy, it doesn't reallymatter which one it is, that inhibits this protein here. it's called akt. and the drug that we haveavailable is azd5363. it's a catchy name, isn't it? but this is a phase 1 study. the drugs are not namedin these phases usually.

if we inhibit this akt proteinin patients whose tumors have an activated pathway,and then as those tumors that have mutations in thesegenes, like pi3kinase or akt, we might see othertumor effects. and this is where your mutationpanel becomes so important. because we can consideryou a candidate for this particular drug if wecan demonstrate the presence of these mutations. if you're not a candidatefor the trial in particular,

they have nowapproved what we call mtor inhibitors that doinhibit this complex shown down the right side. and i have a number ofpatients on mtor inhibitors that have shown, bymutation profiling, that the pathway is activated. and it works in someof those patients. so it's an off label use of thedrug in gynecologic malignancy. and i think if you lookfor clinical trials that

are based on mutation inthe pi3kinase pathway, and a drug that targetsone of the mutations, i think there is somegood evidence that you get some efficacy fromthese type of interventions. another pathways isthe mapkinase pathways. another cause, again, deepinto pathology and biology, but it's anotherprotein cascade. here again, it's theoutside of the cancer cell. it signals into the cell bydifferent proteins like ras,

[? mac, ?] mapkinase,[? irc, ?] and ultimately again, increases the growth of thecell metastatic profile. now what if we inhibitone the central proteins? we just take outone of these enzymes and the cell is deprivedof this pathway? we have drug inclinical trial now. it's called trametinib. and particularlyfor those patients that have what we call a lowgrade serous ovarian cancer,

these drugs might be efficientbecause these low grade serous ovarian cancers usethis pathway to grow. again, that's a trialthat has started. and if you are apatient that faces the issue of having to come upwith an alternative treatment for low grade serousovarian cancer, trametinib might actuallybe a good choice for you. the second principlei want to talk about, and i know a lot of youknow about these drugs,

is targeting thecancer cells that are defective in dnarepair mechanisms. dna is the essence of the cell. so it makes all the proteins,provides information to make the proteins. dna is damaged bychemotherapy and radiation. if you out in the sun,damage to the dna. a normal cell can verywell repair its dna and it ends up survivingany damage and grows.

now a cancer cell often has adefective dna repair mechanism. and upon radiation andchemotherapy, it dies. and that's why, at leastpartially, chemotherapy and radiation is moreselectively killing cancer cells rather than normal cells. now if in addition to beinga cancer cell with already defective dnarepair, these cells are deficient inbrca 1 or 2, they have another hit against them.

because those brca 1 2proteins are much involved in dna repair. so patients whose tumors havea brca deficiency because of a mutation, those tumorsdon't have a great ability to repair their dna damage upontreatment with chemotherapy. and that's why patientsthat have brca mutations, in general, respondbetter to chemotherapy and have a better outcome. but we can use thisto our advantage

by inhibiting yet anotherenzyme in the dna repair pathway called parp. it's a long name-- polyadp ribose polymerase, but it's an important enzymeand a lot of inhibitors are now studied toinhibit this enzyme. if you do it in patientsthat have a brca mutation background, the efficacyis rather impressive. and i'll show youthis in a moment. there's a numberof different drugs.

these one mentioned here areolaparib, niraparib, rucaparib, veliparib. i know it's a verydifferent language. but all of those four wehave used here at stanford. we have from thevery first beginning of the development of thesedrugs put a lot of emphasis on getting this to our patients. and actually, it has shownsome very interesting, promising results.

and i'll show you oneof these studies here. there's a study out ofthe european literature. here are patients that hadrelapsed ovarian cancer. they were treatedwith platinum agents, and had a good response. and then they would giventhis olaparib drug, the parp inhibitor. and this is what we calla kaplan meier curve here. up on top is shownthe patients' survival

that have brca mutations. and that was an averageof about 11.2 months of progression free survival. that's the time that thedisease doesn't get worse. and when you look at thepatients that get the placebo, their survival wasless favorable, with about 4.3 monthsprogression-free survival. so a rather largedifference it was. this was not the data that thefda used to approve olaparip

a few months ago. it was this data here, thatwas published in january, 2015, so a few weeks ago in the"journal of clinical oncology." this is a study that usedpatients with brca mutations, as you can see on theleft side of the table. they had mostly brca 1 mutation,but also brca 2 mutation, and one patientwith two mutations. they had a mean how 4.3 priorregiments, prior chemotherapy, so that's a lot.

four different chemotherapyagents-- those patients are very difficult totreat with any drug. but in brca mutationcarriers, there was a 31% tumor response rate. there were about 6 outof 60 patients here that had a complete response--complete disappearance of all tumor. and 54 patientsout of 60 that had at least a partial response.

and that related an actualprogression-free survival of about seven months, whichin this population, compared to historic controls, meaningother trials they had done prior, is actually aboutthree months better than we had seen before. this was not a trial thatcompared it to anything else. this was just asingle agent trial. but the fda was convincedthat this was actually very promising.

and we can now getour patients that had at least three prior--or four chemotherapies prior this drug approvedand treated with. so again, as i said, at stanfordwe have a lot of interest in further developingthese parp inhibitors. we have a number of trials goingon that use all of these drugs. keep in touch withus about what we open and what is closing,what is available. and this recruitment is actuallyat stanford going very well.

there's great interest. if you don't find parpinhibitors at stanford, and please lookaround, there's a lot of institutions that havethem now in clinical trials. the last section iwant to actually focus on immunotherapy, somethingthat is very much in vogue nowadays because it has showngreat promises in other tumor models, includingmelanoma, lung cancer, some of the data you'reprobably aware of.

now the immune systemis very complex. and i'll show youhere how we look at this as a the innateimmunity on the left side-- a lot of cells that arepart of the rapid responses, we call it. so if you have a cancercell, a virus, bacteria, anything foreign to thebody, these cells get on site and try to fight theforeign invaders. and the other side isthe adaptive immunity.

and this is reallya slow response that the body has to learn. so it has to learnhow these invaders, cancer cells look like. and then make either antibodiesagainst them via b cells, or make specific t cellsagainst cancer cells. and cd8 positive tcells, for example, we call cytotoxic t cells. and those are extremelyeffective against cancer cells.

and i'll show you how we willuse this in clinical trial there's been a lot ofexcitement about modifying t cells from patients,re-infusing them into the patients,and then seeing really fabulous,unprecedented antitumor effects inparticularly lymphoma, and now we're seeing this inother more solid malignancies as well. so there an innate immunity,an adaptive immunity.

and we really have madeprogress in understanding these type of interactions withtumor cells in the patients. now how does actually acancer stimulate an antitumor response? and if you follow me here,it releases certain protein. the cancer cells doexpose certain proteins to the immune system. these proteins and productsof the cancer cells can travel to thelocal lymph nodes.

and they do this viaspecialized cells. and what happensin the lymph nodes, they show themselvesto the immune system. and as they dothis, they activity certain what we call t cells,again, and other cells. and these t cellsare then released in the systemic bloodstream. and in the bloodstream,they find tumor tissue. and at the tumor site,they can potentially

kill the tumor cellsbecause they're activated against the tumor. they have learned how thetumor-- what the tumor looks like. now that in theoryworks very well. and although we finda lot of t cells when you look into a tumor,unfortunately these t cells are prevented fromdoing the killing. and that's a lotof different ways

that these cancercells have found to prevent them from beingkilled by the immune system. i've mentioned a few here. the most interestingapproach now pertains to thepd1 and pdl1 axis. i'm going to show youthis in a moment here. as i said, cancer cells blockthe surrounding immune effector cells. as i said, in thetumor environment

a lot of natural killer cells,t cells, are macrophages. but these cancer cells have allthese stop signals around them. and the t cells and macrophagesjust can't get to them. now what are thesestops signals? one that did was very muchdeveloped here at stanford and studied now in a clinicaltrial is called cd47. cd47 sits on tumorcells and it prevents what we called macrophagesthat a very, very able to digest tumor cellsto do their job.

so they sit there,but they can't do what they're supposed todo-- eat the tumor cells because of cd47. so if you block cd47, you mightactivate these macrophages. the same is truefor the other axis that i just mentioned--the pdl1 or pd1 axis. pdl1 is expressedon the tumor cells. and it stops the tcells from working. now how does it work here, ina more scientific attitude,

again, pdl1 is onthe tumor cells. and pd1 is on the t cells. when these twomolecules connect, you see a decrease in theactivation of the t cells. it just blocks them. so it makes senseto design molecules against this interaction. and we now have a number ofinhibitors against either pd1 or pdl1.

and if you interrupt thatinteraction between these two molecules, the t cellsand the tumor cells, the t cells are not beeninactivated anymore, and can actually killedthose tumor cells. now the process ismuch more complicated, but this is a simpleview of how we think the inhibitionmight actually get us to have activated t cells. we call those immunecheckpoint inhibitors.

the pharmaceuticalindustry is a very active these days to develop anumber of different compounds. i'll show you thenames of these here. nivolumab, pembrolizumab--those a drugs that were early in developmentby bristol-myers squibb, for example. there's other that aredirected against pdl1-- a lot of very promising data. i'll show you some ofthis promising data here.

this is a study thatwas done at ucla by antoni ribas and others. this is a pd1 inhibitor,lambrolizumab, in melanoma. and in a 135 patients,the response rate, this is recurrentmelanoma, was about 38% and the highest was 52%. so a tremendous,really never seen before response to adrug in solid tumors. and more importantly, theresponse was rather durable.

the medianprogression-free survival was longer than seven months. and in a separate trialthat used nivolumab, another pd1 inhibitor, thiswas published about a year ago in melanoma-- 107 patients. again, the medianoverall survival of 16.8 months, response rateswere one- and two-year survival rates of 62% and 43%. those are very advancedmelanoma patients.

and even moreimportant was the fact that even if youstop the treatment, the effect continued. so for some reason, inhibitingthe immune checkpoint led to an educationalimmune system that's lasted for along period of time. so these patients arecontinuing to be followed. you see last few months,a rather large number of other trials coming outthat show that this indeed

is an extremelypromising approach. it looks particularly wellin melanoma, lung cancer, and renal cancer. but we think it might alsowork in other cancers, like gynecologic malignancies,ovarian cancer, for example. here we're shown someprevious studies. on the left uppercorner is a slide that shows you that we findin brown a lot of t cells in ovarian cancer.

but they can't do their jobbecause they're inhibited. in the lower leftpanel here is shown an expression of pdl1 and 2. there's two different formsof that in ovarian cancer. and if you havea high expression of pdl1 in your tumor,you don't do that well. your prognosis is worse. and that really fits the conceptof this protein inhibiting a local immune response.

now we don't have a lot of datagynecologic malignancies yet, as we are startingto study this. but here's oneexample out of japan where they used nivolumab ina platinum-resistant ovarian this is a clear cell carcinoma. and i want to show you thatthese masses here that you see circled in a ct scanright above the kidneys, they're about 6centimeters in size. they disappearcompletely when you treat

the patient with nivolumab. so it's six centimetersbefore treatment. and then at day 79and 123, there's still no sign ofrecurrent disease. this is one of thesecancers that, as i said, is extremely difficult to treat. but this drug seems tohave made a big difference you also see adrop with the ca125 down to a very normalvalue below 35.

in addition to this,this was actually a long-lasting response. now those are singlepatients still. but i think we need to get thesedrugs into gynecologic cancers. and if you lookfor drugs out there for your particular situation,look for pd1 and pdl1 inhibitors. they're often are used incombination with other drugs, but i think here's an areathat they need to focus on.

there's also a way ofredirecting the immune system against cancers. and here is a t cell thatseems to make contact with a cancer cell. and as it does this,it recognizes cells and can potentially kill it. now how do we get a t cellto recognize a cancer cell and kill it? now cancer cells havecertain proteins on them.

they're called antigen. they can be very specific,or not so specific, meaning they're not onlyexpressed on cancer cells, but maybe even on normal cells. but the t celldoesn't necessarily know what to look forunless we instruct it. and we have nowways of doing this by modifying genetically the tcells with a t cell receptor. we're using viruses for this.

we take the t cellsfrom the patients, we infect them with aretrovirus that genetically modifies those t cells. and when they're re-injectedinto the patient, these t cells circulateto the tumor cells. they recognize the tumorcells, and hopefully kill them. and this is what wecall the adoptive t cell therapy that's beenso much in the news in the last few months.

again we are just starting todo this in a ovarian cancers and gynecologic malignancies. it's been done incd90-positive t cell lymphomas in a similar way. we're rolling outa number of trials here at stanford which willinvestigate this principle. and i think here isan approach that, again, is extremely promising. what antigen should wetarget in ovarian cancer?

we have one that we'regoing to start with. it's called theny-eso-1 antigen. the reason why we likeit is because it's not expressed in normal tissue. expressed in the normalovary, but it's not so much of an issuein ovarian cancers. otherwise, it's reallyspecific for cancer cells. and that's why it'sa good target for us. again it's a simple design.

a blood sample is taken. the t cells areextracted, they're genetically modifiedin the laboratory. and then few later, wego back to the patient. it's not quite assimple because you also have to give the patientchemotherapy to suppress their own immune system. otherwise these cellswill not take a very well and will disappearedvery quickly.

so i want to show you inthe last couple of slides that we have a number oftrials open here right now. again call ashley,sharamya, bela. they will give youmore information. we have parp inhibitortrials opened. we have trametinibopen that is low grade serous ovarian cancers,as i showed you, does inhibit themapkinase pathway. we have new drugs herethat do prevent, hopefully,

stem cells from signalling. that's called omp-54f28. it's a phase 1, 2 trial. and then again therucaparib for the treatment of platinum-sensitivedisease that relapsed after three, but not more thanfour lines of chemotherapy. so that's for ovarian cancer. we have currently one trialfor endometrial cancer that will investigate whethermetformin-- it's usually

a drug used for diabeticpatients-- makes a difference when added to astandard chemotherapy. and then as i mentionedbefore, an akt inhibitors in patients that havean activity pl3kinase pathway. and we do this in differentmalignancies, women's cancer, ovarian, endometrial,cervical, and breast cancer. but it does require that weprofile your tissue, your tumor tissue, for the presenceof certain mutations. we have work a numberof trials for this year.

and again, my researchgroup is working very actively of opening anumber of trials so stay tuned. we're going to putthem on the website. again, i am particularly excitedabout the adaptive t cell therapy that targetscertain specific antigens. and hopefully, we'll havethis available for you in the very near future. so in summary, ithink that i hopefully have shown you that theclinical trials for cancer

are carefully designedstudies in human subjects that assess an intervention thatwill ultimate provide a greater benefit to the patientcompared to existing therapy. that's really our goal. it should be more efficacious. we should be able to improvethe prognosis of a patient, give them longevity, witha good quality of life. i think, again, that the cancerinstitute here at stanford has done a fabulousjob providing you

with access to informationabout clinical trials. we have the website andthe app for your iphones, and the nih clinicaltrials.gov website provide excellentresources, if you want to look for trialat stanford and beyond, even worldwide. as i said, i think some ofthe promising developments for gynecologic cancers,and for other cancers, come from targeted therapies.

for example, targetingpi3kinase and mapkinase pathway, parp inhibitors,and immunotherapy. if you have a question, and iknow it gets very complicated, please don't hesitate to callus for advice and information. this talk will beavailable on youtube. so you can reviewit if you like to, and at least get thepertinent information. i want to point outthat this is not possible without thehelp of many people.

here shown is the stanfordcancer institute executive team, which is reallyheaded and vouch-supported by our dean, dr. lloyd minor,and also beverley mitchell, the director of thestanford cancer institute. this can only work with a bigsupport of everybody that works together here at stanford. i want to particularlyalso acknowledge the people that i work with more closelyat the stanford women's cancer center.

this is dr. jonathanberek the chairman, who wanted to be here tonight,but has a different commitment. katherine bailey, who runsall the cancer care programs, and then our facultyhere-- i think you have seen enoughof me tonight. but this is dr.amer karam, who is an excellentgynecologic oncologist, has a focus on roboticsurgery, but also development of clinical trials.

dr. nelson teng, who isa very established figure and very [? expansed ?]gynecologic oncologist, dr. shannon mclaughlan--all of us are very happy to talk toyou about clinical trials and enroll you in those. and likewise, our brigidmiralda and aarthi who are both excellentnurse practitioners and are very happy to talk toyou about any questions you might have about clinicaltrials in our division

at the stanfordwomen's cancer center. so i'm going to close it upwith a couple of pictures . here it is, the stanford woman'scancer center and the stanford this is where wetreat our patient. this, of course, is a beautifulpicture of our campus. i want to thank you again forbeing in attendance tonight. and i'm happy to answer anyquestions you might have. just one question. how well versed arepatients-- looking

at this inclusion and exclusioncriteria, it's self-identifying in calling your center? so it's a very good question. why can you read theinclusion exclusion criteria? i think a lot depends on howmuch a patient knows, how medically informed they are. the second issue pertains tohow well they are written. some of them are written, andyou guys can confirm this, in very medical terms.

and then they comeso technically that it doesn't reallyrequire a phone call. i would recommendthat before you think you're not a candidate forthe trial, call us and ask us. because some of the thingsthat are written in those criteria might be misunderstood. some of this also pertainsto certain laboratory values that you mightknow as a patient. and again, that requiresanother blood test

or requires anotherimaging study. a lot of our studies need whatwe call measurable disease. you want to see onct scans some mass some lesion that we can follow. let's say there's a 3centimeter nodule in the pelvis. a lot of trialshave the requirement to have such a measureon know you're available. and when you enroll, youneed to show a ct scan or actually do a ctscan that measures this.

and you can follow thisin ct scan over time. and that's not necessarilythe information that you as a patientmight have in your hands. does that make sense? in terms of calling,i think patients are very good about calling us,getting the information we're trying to provide them,and any information they need for gettingwhere they need to be. and i think the websitesare very useful at least

to find trials. and the algorithms, i encourageyou to use those as well, where you type in veryspecific information about your particular situation. and you can channel downon the many, many trials that you can chose from. any other questions? we're always here for you. we have i think ourphone numbers everywhere.

you can also reach us via email. so if there's noother questions, then thank you everybodyfor attending tonight. and i hope you havea good way home.