Experimental Therapeutics

March 01, 2021

Information

February 28, 2021

Yale Cancer Center

visit: http://www.yalecancercenter.org

email: canceranswers@yale.edu

call: 203-785-4095

ID6236

To CiteDCA Citation Guide

00:00Support for Yale Cancer Answers
00:02comes from AstraZeneca, dedicated
00:05to advancing options and providing
00:07hope for people living with cancer.
00:10More information at astrazeneca-us.com.
00:14Welcome to Yale Cancer Answers
00:16with your host doctor
00:17Anees Chagpar. Yale Cancer Answers
00:20features the latest information on
00:22cancer care by welcoming oncologists and
00:24specialists who are on the forefront of
00:26the battle to fight cancer. This week,
00:28it's a conversation about experimental
00:30therapeutics with Doctor Pat LoRusso.
00:32Doctor LoRusso is a professor of
00:34medicine at the Yale School of Medicine,
00:37where Doctor Chagpar is a professor
00:40of surgical oncology.
00:41Pat,
00:42maybe we can start off by you telling
00:44us a little bit more about what
00:48exactly is experimental therapeutics.
00:50It sounds so obscure and
00:52intellectual and scientific and strange.
00:55It isn't obscure for
00:56me. I think it is somewhat intellectual,
00:59and it is very scientific,
01:01and so I hope that I'll be able to
01:05explain to you what all that means.
01:08So with every cancer drug that we have,
01:12that we treat patients for, every cancer
01:14drug that's commercially available,
01:16it has to go through a series of testing not
01:20only in the lab to identify its activity,
01:23not only in other animal species,
01:26to make sure that it is safe
01:28to administer to humans,
01:30which are called toxicology studies,
01:32but then it has to go through a series
01:35of tests in humans first to make
01:38sure that the drug is safe to give,
01:42and then to find
01:45out how active it is,
01:47either alone or in combination
01:50with other agents.
01:52So Phase one clinical trials
01:55are essentially trials
01:58whereby a new drug is tested
02:01for the first time in humans.
02:06Although the primary objective of a
02:09phase one trial is actually to make sure
02:12that the drug is safe to give to humans.
02:15We are also looking for a lot
02:18of other endpoints as well.
02:20What kind of activity does it have
02:24against specific tumor types?
02:26How is the exposure of the drug
02:28in man relative to what we saw
02:32previously in various animal species
02:34and to assure that we have the
02:37utmost safety in these trials.
02:39Obviously all trials have to be approved
02:42by the Food and Drug Administration
02:45before they can be initiated in humans,
02:48and that is the same thing with a
02:51phase one or first in human study.
02:54But what they do
02:56is based on animal trials previously
02:59done with the agent and toxicology
03:02studies that are also previously done.
03:05The FDA works with the sponsor
03:08or the drug company to identify
03:11a safe starting dose.
03:13A dose where we can feel quite
03:17assured that giving that dose will
03:20be safe to humans and to identify
03:23what the most relevant dose will be
03:27to go into subsequent phase two and
03:30three trials and then hopefully to
03:33go into FDA approvals for standard
03:36of care treatment.
03:38We do various escalation steps along
03:40the way to identify a safe dose that
03:45can be subsequently brought into a phase
03:48two efficacy or a phase
03:50two comparative efficacy study
03:52which may take anywhere from 3 to
03:5510 or 12 escalation steps.
03:58So that we're gradually increasing
04:00the dose to the point where we
04:03identify what a safe dose is that can
04:06be subsequently advanced to other
04:09phases of clinical trial development.
04:15So this is really important work,
04:18because this is how we get the drugs into
04:22the clinics that actually provide the
04:25cures that all of us want for cancer.
04:29But it really starts very much in the lab,
04:33so help me to understand and
04:36help our listeners to understand
04:38what goes into
04:42getting a drug even into phase one
04:44because as you describe it Phase
04:47one clinical trials maybe seem
04:49really scary to a lot of patients.
04:51I mean this concept of being
04:53quote first in man.
04:54Many people are thinking
04:57why would I want to be the first
04:59ones for you to experiment and
05:01see what is safe and what is
05:04tolerable and what is efficacious?
05:06So let's take a step back before that
05:09and kind of lay the groundwork for me
05:12in terms of what goes on before that.
05:14How do we get
05:16to the point of a phase one trial
05:19where you're presenting data to
05:22the FDA?
05:26First a drug is developed in the lab based on a
05:30scientific principle or a scientific concept.
05:33So I think the best way to describe
05:37it would be to use an example.
05:40So in many tumor types,
05:42primarily non small cell lung
05:45cancer and colorectal cancer,
05:46but other tumors as well,
05:49there is a mutation called KRAS G12C.
05:53And that mutation in large part drives that
05:56tumor and makes it extremely aggressive.
05:59It's taken many, many,
06:01many years for chemists to develop a
06:05drug that can target or inhibit that
06:09mutation from continuing to allow
06:13the tumor to multiply and divide.
06:17So that drug probably
06:19took about 20 years conservatively of
06:22chemists working on trying to figure
06:24out how to target that mutation,
06:27which was extremely difficult
06:29because of the way that mutation is
06:32pocketed in the DNA of the tumor.
06:35Once they identify a compound that can
06:39bind to that mutation
06:41or attack that mutation,
06:43then they have to test it
06:45in animal models,
06:46tumors in animals that have that
06:49mutation to see whether or not the drug
06:52is going to work against those tumors
06:54inhibit those tumors from growing,
06:57preventing those tumors in animals from
06:59metastasizing or going beyond where
07:02the tumor was originally implanted.
07:05Once they do that,
07:06and identify that the drug is active,
07:09then we have to take it into
07:11toxicology studies where we test the
07:14drug in different animal species
07:16to make sure that
07:18we can safely give
07:20that drug to the animals without
07:23causing side effects or harms,
07:25and we usually have to do that in two
07:28or three different animal species,
07:30depending on what the drug is.
07:32But back in the olden days I call
07:35it when I first started doing
07:37clinical drug development,
07:39during development of drugs in humans,
07:42we didn't have the scientific
07:44basis that we have today and today
07:48there's a lot of science that is
07:51driving new drug
07:54discoveries in the lab,
07:56especially with targeted drugs
07:58because of the fact that unveiling
08:01the human genome several years ago
08:04allowed us to better understand the
08:07differences between the DNA and RNA.
08:10In tumors versus the DNA and RNA in
08:13the normal human and what we had to
08:16go after in those tumors to prevent
08:19them from growing and hopefully from
08:22prevent them eventually from even coming
08:25about in patients that may be high risk,
08:28such as in prevention,
08:29but no matter where the drug ends
08:32up treating advanced stage patients,
08:35patients that have cancer
08:36that's metastasized,
08:37or patients that have had cancer,
08:40but we've removed the tumor.
08:42And we want to prevent the
08:45cancer from coming back.
08:46Every drug that's given to humans in
08:49a general oncology office has to at
08:52first be tested in early phase clinical
08:55trials and back in the olden days.
08:58You know,
08:59we tested a lot of drugs based
09:02on just these high throughput
09:04screens in mouse models without a
09:07lot of science, there was science there,
09:10but today, in 2021 the science
09:13has advanced much more
09:15that we are even selecting
09:17out certain tumor types.
09:19Patients that have certain types
09:21of cancers based on the science.
09:24Because we know even in phase one
09:26trials that we may have a greater
09:29chance of response and benefit if we
09:33only treat patients with those tumors.
09:35Going back to the KRAS G12C mutation
09:39that I was talking about a few minutes ago,
09:43we only included in those phase one trials
09:46patients that we knew whose
09:50tumors had that mutation and in non
09:53small cell lung cancer in a phase one
09:57trial we were seeing close to 70-75%
10:00tumor response and in colon cancer,
10:03in patients who had colon cancer
10:06that had the KRAS G12 C mutation,
10:09we were seeing responses about 40 to
10:1350% and many of those patients had a
10:16lot of prior treatments either immunotherapy,
10:20chemotherapy,
10:21or both and yet despite having all those
10:25different cancers be treatments because
10:27their cancers had that one mutation,
10:30there was significant benefit as early
10:33as in the Phase one clinical trial.
10:37So even though these trials
10:39are primarily toxicity
10:41finding studies and finding
10:43the recommended phase two dose
10:46many times in these trials,
10:48if we have a specific target that
10:51we're targeting and we can identify
10:55patients whose tumors have that target,
10:58there is a potential therapeutic
11:00benefit for those patients
11:03either in terms of their tumors
11:05shrinking or staying stable for
11:08a prolonged period of time,
11:09even at some of the lower doses,
11:12because as I said,
11:14we have to start low and go high,
11:18and with the initial drug that targeted
11:21KRAS G12C, responses were seen
11:23regardless of what the dose was,
11:26which is extremely encouraging
11:27and that drug is moving forward
11:30hopefully to FDA approval.
11:33So I think that there's a few
11:35things there that you said that
11:38are so important to highlight,
11:40one of which is that our ability
11:42now to to figure out what the exact
11:45mutations are and to develop drugs
11:48that will target those mutations
11:50really not only benefits
11:52patients in terms of
11:55lack of side effects and potential
11:57better efficacy of a drug that
12:00targets a particular tumor,
12:01but it also really encourages
12:03patients to participate in
12:05clinical trials because you know
12:07that that drug, at least in animal models,
12:10has been shown to be efficacious
12:13against that particular mutation,
12:14and at least in animal models,
12:17doesn't have high toxicity.
12:18And so Pat,
12:20when you're designing a phase
12:22one trial and thinking about
12:24the patients who are eligible,
12:26I think the other thing that was really
12:29critical that you said was not only
12:32how you target the population to
12:35those patients who could
12:37potentially benefit from this,
12:38for example,
12:39those who have a specific mutation.
12:42But also those for whom
12:45standard of care may be falling
12:47short where there may not be other
12:50options who have been through
12:52a number of series of different
12:54regiments and have come to exhaust
12:57standard of care options tell us more
13:00about how you go about designing a
13:02phase one trial in terms of who's
13:05eligible and how
13:08many patients are eligible and how
13:10you kind of figure out how many patients
13:14you need to have on that trial
13:16to get the information that you
13:18need before you can open this up
13:21to wider clinical trials?
13:23Right, so first of all,
13:25there are a limited number of
13:27patients that go on the phase
13:30one trials because we're really
13:32looking for potential side effects
13:34of the drug to make sure that the
13:37drug is safe to give to patients.
13:40So we slowly increase the dose will
13:43treat one to three patients and we'll
13:45have to get them through at least
13:48three to six weeks of treatment
13:51before we then can increase the dose
13:54and add another one to three
13:56patients as an example.
14:00And so I wanted to pick up
14:02on all of the things that we
14:04look at in terms of Phase one,
14:07clinical trials and how we actually
14:09get these drugs to market right
14:11after we take a short break
14:13for a medical minute.
14:15Please stay tuned to
14:16learn more with my guest Doctor Pat LoRusso.
14:19Support for Yale Cancer Answers
14:21comes from AstraZeneca, working to
14:24eliminate cancer as a cause of death.
14:26Learn more at astrazeneca-us.com.
14:29This is a medical minute
14:31about smoking cessation.
14:32There are many obstacles to
14:34face when quitting smoking
14:36as smoking involves the potent drug nicotine.
14:39But it's a very important lifestyle change,
14:42especially for patients
14:43undergoing cancer treatment.
14:44Quitting smoking has been shown to
14:47positively impact response to treatments
14:49decrease the likelihood that patients
14:51will develop second malignancies
14:53and increase rates of survival.
14:55Tobacco treatment programs are
14:57currently being offered at federally
14:59designated Comprehensive cancer centers
15:01and operate on the principles
15:02of the US Public Health Service
15:05Clinical Practice guidelines.
15:07All treatment components are evidence
15:09based and therefore all patients are
15:11treated with FDA approved first line
15:13medications for smoking cessation as
15:16well as smoking cessation counseling
15:18that stresses appropriate coping skills.
15:20More information is available at
15:23yalecancercenter.org. You're listening
15:24to Connecticut Public Radio.
15:26Welcome
15:26back to Yale Cancer Answers.
15:28This is doctor Anees Chagpar
15:30and I'm joined tonight by
15:32my guest doctor Pat LoRusso.
15:34We're talking about
15:35experimental therapeutics,
15:36and phase one clinical trials,
15:38and right before the break,
15:40Pat, we were talking about how you
15:42go about designing these phase one
15:45first in man clinical trials and
15:47we were talking about the fact that,
15:49you know, it seems to me to be a little
15:53less scary than it was in previous years.
15:56Because drugs these days are so much
15:59more targeted and there is a lot of
16:02regulation and a lot of preclinical
16:04work in terms of animal studies,
16:07that goes into really making sure that
16:09these drugs are efficacious and not toxic,
16:12at least in a couple of animals
16:15species before it ever hits
16:17phase one clinical trials.
16:19But you were starting to tell us right
16:22before the break about how you design
16:25these phase one clinical trials.
16:27How many patients you involve,
16:29what your inclusion criteria are,
16:31the safeguards that you put
16:34around these trials.
16:35Because still, for some patients,
16:37this may seem really scary and
16:40often is used as a last resort,
16:43so can you
16:44talk a little bit about that?
16:48Oh yes,
16:49absolutely. And thank you for the
16:51opportunity to do so. So to begin with,
16:54how do we design these trials.
16:58In terms of finding the dose that we want to
17:01start with and how we're going to escalate,
17:05that pretty much comes from the toxicology
17:08studies that we've done before we get
17:10into the clinic before we go in demand.
17:13But also exposure of the drug.
17:15So what was the exposure that was needed
17:18in the various model systems that we
17:21used in order to see benefit to see
17:24the tumor regress either in the mouse
17:27models or in the in vitro Petri dishes?
17:30Because we know that we have to start safe.
17:34But we also want to make sure that
17:36we can get to an adequate exposure,
17:39because if we can't get
17:41to an adequate exposure,
17:43we are concerned that we may not see the
17:46benefit and oftentimes there is a very
17:48large what we call therapeutic window,
17:51a window or a dose at which we started to
17:55see activity to a dose where we saw side
17:58effects in animals and
18:01the easier it is for us to identify how
18:05fast we're going to increase our doses.
18:08Another thing is we look at the inclusion and
18:12exclusion criteria and in terms of toxicity,
18:15if we know that the drug preclinically in
18:18animals led to some type of a side effect,
18:22we have to select out our
18:24patients based on that,
18:26or do some additional tests to make sure
18:28we can hopefully safeguard patients and
18:32follow them closely so that
18:34they don't have a side effect.
18:37But in terms of efficacy as well,
18:39it would not be
18:42in 2021 because we know so much more
18:44about the science and how the science
18:47is driving the tumor in humans,
18:50we want to select out patients that will
18:52have the greatest chance of benefit.
18:55So back 25 years ago when I
18:57started doing Phase one trials,
18:59we would do what we called all comer studies.
19:03All patients, regardless of the tumor,
19:05were allowed to go on phase one trials.
19:08Because we didn't know enough about the
19:11science that was driving particular tumors.
19:14And nowadays in 2021 it's not
19:16uncommon for us to design a trial
19:19that may only have two tumors,
19:21or maybe two tumors and a third
19:24arm of tumors that have a specific
19:27mutation an like the KRAS G12C
19:30story that I was telling you about.
19:33We knew that the primary tumors that
19:36we needed to go after were the lung
19:39tumors that were either lung cancer
19:42or colon cancer that harbored
19:44this KRAS G12C mutation.
19:47But there are other tumors that
19:50rarely harbor this mutation as well.
19:52Cholangiocarcinoma,
19:53you know various tumors and so we
19:57allowed a third arm or a third
20:00basket of tumors to be enrolled
20:03of those different tumors that
20:05might have that mutation.
20:06Additionally,
20:07back in the olden days,
20:09we used to see patients that had failed
20:12everything, even drugs that really
20:14were not doing that much for them,
20:17but might have been FDA
20:19approved for commercial use.
20:21But nowadays we realize that
20:23that may not be the best patients
20:25to put on these studies,
20:28especially seeing that
20:29we're targeting science.
20:30And we're not looking necessarily for
20:32patients now that have exhausted everything.
20:35But like for instance,
20:36we have a trial that only wants
20:39patients that have failed what we call
20:42frontline therapy for colon cancer or
20:44frontline therapy for pancreas cancer.
20:46Only one treatment for their
20:48metastatic disease,
20:49and then we want to bring them on
20:52the trial because we know that
20:54the farther out you go in terms
20:57of number of different treatments
20:59that a patient is given,
21:02many times there's a significant
21:05decrease in the ability for that tumor
21:07to respond to a certain treatment,
21:10and so we're requesting even in early phase
21:14once we've gotten to that dose that
21:16we want to advance forward instead of
21:19just going right into a phase two,
21:23we may do what we call expansion cohorts.
21:26In that phase
21:27one trial and where we put only
21:30patients with colon cancer,
21:32or only patients with ovarian cancer.
21:35And only those that may harbor as an example,
21:38a certain mutation.
21:40Because we want to move the drug
21:43through as quickly as possible,
21:45but as safely as possible so that
21:48we can hopefully advance that drug
21:51right into a phase three trial,
21:54which is a randomized trial looking
21:56at standard of care versus the new
22:00drug or standard of care versus
22:02standard of care.
22:04Plus the new drug together so that
22:06we can hopefully advance that drug
22:09to commercialization to make it accessible
22:12to all patients that could benefit
22:15from that drug as quickly as possible.
22:18Yeah, I think that's so important right
22:21in thinking about the fact that even if
22:24you look at our standard chemotherapies,
22:27many of these are drugs that were
22:31developed back in the quote the good old days,
22:34which really aren't targeted and now
22:37that we have these targeted therapies
22:40it may be patients who
22:43have specific mutations.
22:44To really look at clinical trials before
22:48they've exhausted all of their options.
22:51So Pat, my next question is,
22:55do you find that patients are still
22:58resistant to looking at clinical trials?
23:01Do they have enough information
23:03about where to find these clinical
23:06trials and for the people who
23:09are listening on the radio today
23:11who may be thinking,
23:13I failed my first round of chemotherapy,
23:16or maybe even two rounds,
23:21and you know,
23:22how far do we keep going down the
23:24line thinking about the next line of
23:27therapy in the next line of therapy,
23:30all of which may be less effective
23:32versus trying a clinical trial.
23:34And how do I get information about
23:37what clinical trials are out there that
23:39might be well suited to me in my tumor?
23:45In the Connecticut area obviously you
23:47know Yale Cancer Center is an
23:50outstanding resource for clinical trials.
23:52And you know, contacting somebody
23:54at Yale Cancer Center,
23:56if you have a GI cancer
23:59cancer of the colon or stomach,
24:02contacting the GI team to see
24:05do they have trials available?
24:07Or if you have metastatic disease, your cancer
24:10is spread outside of its primary source,
24:13contacting our team as an example,
24:17and if you contact Yale,
24:21they will get ahold of the right physician
24:23to be able to answer those questions.
24:27You can also go on cancerclinicaltrials.gov,
24:29a website that is
24:32sometimes very difficult to maneuver.
24:35You can ask your primary oncologist,
24:37but depending on how comfortable
24:39they feel in referring you,
24:42you're at the disposal and
24:45you're at the mercy of them sending you
24:48for a second opinion or sending you to
24:52a site that may have clinical trials
24:55that may not be available to them.
25:00Sometimes it's very difficult for
25:03these patients to find these trials.
25:06Unfortunately,
25:07of all patients that are diagnosed
25:10and treated for cancer,
25:12less than 3% of them are ever
25:15put on a clinical trial,
25:18and there are certain communities
25:21of patients,
25:22the underrepresented minorities,
25:23those patients in rural communities
25:26that have the greatest
25:30impact of not being offered
25:33a clinical trial or not being able
25:36to get access to a clinical trial.
25:39So I mean,
25:40there are some organizations
25:42that you can contact
25:44that may help you find a trial
25:48or calling the NCI directly,
25:50but many times it's difficult
25:53unfortunately,
25:53to even maneuver those
25:55avenues of information.
25:58So Pat, you mentioned underrepresented
26:00minorities and I just want to pick up
26:04on this just for a minute because
26:06for many patients who may be
26:09from underrepresented minorities
26:10African American patients,
26:12for example, they may be reluctant
26:15to participate in clinical trials
26:18given historical events
26:20that have happened in this country,
26:23which have been deplorable in terms of
26:27clinical research and how it was conducted,
26:30can you alleviate some of their fears
26:34and anxieties?
26:37Because of some of those
26:40previous events that occur,ed
26:42especially with minority populations,
26:45the Food and Drug Administration
26:48the FDA has put very strict rules
26:51and regulations in place that
26:54will prevent that from happening.
26:57And in fact, there are many investigators,
27:01epidemiologists and scientists
27:02that are trying to understand
27:05why underrepresented minorities
27:07are not as well represented and the
27:10number one reason is because they
27:12are not offered a clinical trial.
27:15One of the other reasons is
27:18geographic and financial barriers.
27:20Those are two of the other reasons,
27:24but it isn't because they've
27:26necessarily refused a clinical trial,
27:29the lack of being offered
27:32far outweighs their refusal.
27:34The geographic barriers far
27:36outweigh their refusal,
27:38and in fact there are very,
27:41very slim statistics of the
27:43last 17 FDA approved
27:46cancer drugs and less than 4% of all
27:50patients that were recruited were black,
27:53less than 4% of all patients
27:57recruited were Hispanic,
27:59and those two underrepresented
28:01minorities represent a significantly
28:04larger population of cancer patients.
28:06And it's important to have
28:10underrepresented minorities offered
28:12and participate in clinical trials
28:15because we need to see if their tumors
28:19respond the same way their
28:21tumors may have some genetic,
28:23or some germline
28:25mutation or differences
28:27and we need to understand that
28:30and how it impacts their tumors.
28:35I think that's so important because
28:38at the end of the day,
28:40once all of these trials are done and these
28:44drugs are marketed as standard of care,
28:47these patients are going to receive
28:50these same therapies that may
28:52have been developed on a
28:54completely different population.
28:58So Pat very quickly in our last minute,
29:00I just want to get one last question in
29:03which is you mentioned financial barriers.
29:06Are clinical trials covered by
29:08insurance or do people have to pay
29:10out of pocket for these drugs?
29:13The drugs themselves,
29:14if they are investigational drugs,
29:18they do not have to pay for them.
29:21They will be given free
29:23of charge by the sponsors.
29:26Medicare coverage analysis
29:27covers a lot of the tests that
29:30are needed for clinical trials,
29:33but I think some of the greatest
29:36financial barriers are commuting
29:38back and forth to places
29:40some of the standard of care
29:43copays that are required,
29:45and hopefully we will be able
29:48to work towards getting a lot of
29:51those things funded through new
29:53initiatives that can help patients.
29:56Because the patients that need
29:58these studies the most sometime
30:00are patients that do have
30:03a problem gaining access to their
30:05copays or paying a babysitter so
30:07that they can go and
30:10participate in these clinical trials,
30:12or drive or pay for parking at the
30:15sites that they have to be treated.
30:20Doctor Pat LoRusso
30:20is a professor of medicine
30:23at the Yale School of Medicine.
30:25If you have questions,
30:27the address is canceranswers@yale.edu
30:29and past editions of the program
30:31are available in audio and written.
30:33Farm at yalecancercenter.org.
30:34We hope you'll join us next week to
30:37learn more about the fight against
30:39cancer here on Connecticut Public Radio.