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March 19, 2014 at 12:19 pm #21879
Frequently Asked Questions about MK-3475 U.S. Expanded Access Program
s this a clinical trial?
This is not a clinical trial; however similar to a clinical trial, the EAP has criteria for determining which patients are eligible to participate. Information on safety and efficacy will be collected, but far less information than is usually collected in a clinical trial that is conducted to support FDA approval of a drug.
Does the program enroll like a clinical trial?
Yes, the program enrolls like a clinical trial in that patients must meet certain criteria in order to be eligible to participate, and that enrollment is on a first-come, first-in basis. However, the entry criteria for the MK-3475 EAP are broader than for the current or previous clinical trials.
How long will it take to enroll/receive MK-3475?
How long it might take to receive MK-3475 through the EAP will be different for every patient. The timing can be affected by a number of factors, including:
when a physician submits the information on behalf of the patient;
whether any follow up is required to review that application;
how many other patients are enrolling; and,
approval for the program by the local Institutional Review Board.
Will there be an accelerated IRB approval for clinical trial sites?
That will be determined by each site, but we would expect many to seek accelerated IRB approval.
Do participants have to be a U.S. citizen?
Nationality is not a criterion for the MK-3475 EAP. Patients cannot apply to the EAP on their own. Patients must work through their physicians to apply and physicians must be based in the U.S. to participate in the U.S. program.
Where are the sites that participated in the MK-3475 clinical trials?
There are approximately 50 sites across the U.S. participating in the MK-3475 melanoma clinical trials (i.e., KEYNOTE 001, 002 and 006). The list of clinical trial sites is available through Idis, Merck’s partner vendor administering the program, and on
http://www.clinicaltrials.gov. How can I enroll?
Patients must work through their physicians to apply. Patients cannot apply for the EAP on their own.
• Physicians in the U.S. who are interested in enrolling a patient in the EAP should contact Idis at 1-855-478-4347 or via email at
• The Expanded Access Program will expand to other countries in 2014. While we are not yet accepting applications on behalf of patients outside the U.S., Idis will be maintaining a list of inquiries so you can be contacted if the EAP becomes available in your country. The numbers for outside the U.S. are +44 (0)1932 824 123 or via e-mail at
Which physicians will be eligible?
For approximately the first two months, the program will be available through physicians at MK-3475 clinical trial sites in the U.S. Following this initial phase, the program will be open to all physicians in
– 2 –
the U.S. who have experience using systemic immunotherapy treatment for advanced melanoma patients.
Are patients from the control arms of any MK-3475 studies eligible?
No, patients who were on the control arm of any MK-3475 studies are not eligible to participate in the expanded access program.
Is this drug approved by the U.S. Food and Drug Administration?
Do eligible advanced melanoma patients have to pay for MK-3475 in the EAP?
Patients in the U.S. who receive MK-3475 through the EAP will not have to pay for the medicine for as long as they are receiving MK-3475 through the program. Merck is in the process of seeking approval for MK-3475 in the USA. If and when the drug is approved by FDA, Merck plans to provide MK-3475 through the program for a transition period after approval.
Will there be a fee for office visits?
It is possible that there will be a fee for office visits. This is determined by the physician and his or her medical center/hospital. Whether insurance will cover office visit fees associated with participation in the program is a decision made by insurance companies directly.
Under the inclusion criteria, which systemic therapies must patients with advanced melanoma have received previously to be eligible for the EAP?
Patients must have failed or progressed on standard of care systemic therapy (i.e., chemotherapy, immunotherapy). Also, patients must have failed or progressed after treatment with ipilimumab. If a patient is known to have a mutation in BRAF they must have been treated with either a BRAF inhibitor or MEK inhibitor; they do not need to have been treated with both.
Under the exclusion criteria, if you are not BRAF mutant, do you need to have previously received a systemic BRAF or MEK inhibitor?
No, only patients with a positive BR
AF mutation need to have received such treatment.
Under the exclusion criteria, who decides the exclusion criteria for adverse events? Does the physician make this decision?
Yes, the physician will grade the adverse event using the Common Terminology Criteria for Adverse Events (CTCAE).
Under the exclusion criteria, what does “treated brain metastases” mean?
Advanced melanoma patients with brain metastases who are clinically stable, post-surgical resection or radiation therapy are eligible. Patient with active CNS metastases and/or carcinomatous meningitis are ineligible.
What is an expanded access program?
An EAP is designed to provide a patient with access to a medicine before it is approved by a national health authority and outside of the clinical trial setting. For diseases that are immediately life-threatening and alternatives for treatment are either absent completely or have been exhausted, if one of our medicines has shown what appears to be a favorable benefit risk profile in an indication, Merck may create an EAP to help patients with the relevant condition and for whom access to a clinical trial is not possible. The type of program can vary by country, even for the same medicine.
# # #March 19, 2014 at 3:15 pm #63848jamesaParticipant
As usual, you did an “excellent” job getting information for everyone. You are remarkable.
You mentioned “Patients must have failed or progressed on standard of care systemic therapy (i.e., chemotherapy, immunotherapy”. Does that include other pd1 & pdl1 trials other than Merck, that patients have failed or progressed. I am hoping that is the case for people like Jonathan and others.
JamesMarch 19, 2014 at 5:39 pm #63849crburton28Participant
Do you know when this will actually start?
My husband recently became resistant to the BRAF and the cancer is coming back with a vengeance. He will be trying chemist next week to try and tide him over until this gets up and running.
CarlaMarch 19, 2014 at 6:44 pm #63850
James, all other PD1 progressions are eligible (i.e. Curetech and BMS Pd1 failures)
Carla, this may take a few weeks. You should find the nearest site to you and contact them and make sure you get a slot and they can give you an idea of start up time. The links to the agencies running it are listed above.March 19, 2014 at 7:37 pm #63851
In case it isn’t clear, which it wasn’t for me: you must have progressed on IPI and if you are BRAF positive, progressed on a BRAF drug too.March 19, 2014 at 11:29 pm #63852njreadersParticipant I’m concerned about the exclusion for brain mets. Who else is this program for but for people who have cancer anywhere??? Some of my husband’s brain tumors shrank, some are stable and some might have grown but it could be Yervoy ‘pseudo-progesson”. I’m concerned he’ll be excluded when he needs it asap.March 20, 2014 at 4:16 pm #63853PatWParticipantnjreaders wrote:
I’m concerned about the exclusion for brain mets. Who else is this program for but for people who have cancer anywhere??? Some of my husband’s brain tumors shrank, some are stable and some might have grown but it could be Yervoy ‘pseudo-progesson”. I’m concerned he’ll be excluded when he needs it asap.
Active brain mets are excluded from almost all clinical trials. It is rare to find a clinical trial that will allow people with brain mets. I suspect that the reason for this is that the body has a poorly-defined mechanism that prevents most substances in the blood from getting into the brain. It’s called the “blood-brain barrier”. If patients with active brain mets are on a clinical trial but the drug or treatment being investigated can’t get into the brain because of the blood-brain barrier, that won’t help the patients. Furthermore, their progression will mess up the trial statistics for everybody. Therefore, people with brain mets are usually excluded. Sad but true.March 20, 2014 at 5:53 pm #63854Celeste MorrisParticipant
When thinking about the use of novel therapies (ipi and anti-PD1) in regard to brain metastasis, studies and the method of action of these drugs make it clear that the action upon brain mets is NOT due to the DRUG “crossing the blood brain barrier,” but for the activated cytotoxic T-cells to do so. In my own study of resected metastatic melanoma patients with Nivo, all 6 of us who had metastatic brain mets out of the 30 in our arm, begun in 2010, were still alive and kicking with NO RELAPSE as of September 2013. Weber and many other researchers have contended for some time that drugs like Ipi and anti-PD1 have as good an effect in the brain as they do in the body. Additionally, in a nivo treatment arm at Moffitt that allowed brain met patients, 1 of the patient’s brain mets resolved on nivo ALONE…with NO OTHER TREATMENT. To say they are excited is a definite understatement!
In his presentation and interview @ ASCO, June 2013 –
Melanoma: Long overall survival in patients receiving Nivolumab , …When asked about the likelihood that the drug works on brain metastases, Sznol noted that this trial excluded patients with active brain lesions, but accepted patients with previously-treated central nervous system tumors. Therefore the answer to the question remains unknown. “But we have long-term responders who didn’t develop any brain metastases, so that suggests that maybe we are controlling disease in the brain,” he said. Phase II trial of ipi monotherapy in melanoma patients with brain metastases, by Lawrence et al.
Ipi has a similar level of activity in brain and non-CNS lesions. Novel treatments for Melanoma brain Metastases, by Kenchapp et al. 2013. Looked at a study using ipi.. .”this study revealed that ipi has activity in melanoma brain mets…it is unknown whether the treatment was more effective in larger melanoma brain mets in which the highly permeable blood brain barrier may allow greater ingress of activated cytotoxic T cells.”
Melanoma Brain Metastases: Is it time to reassess the bias? By: Flanigan, Sznol, et al. July 2012. These authors note that melanoma brain met patients are typically excluded from trials. They conducted a chart review of 251 metastatic melanoma patients diagnosed after 2005 to evaluate them in the context of eligibility for treatment with novel agents. And “found median survival of malignant effusion (mets in the pleural cavity) patients was significantly shorter than brain met patients (2 vs 8 months).” Therefore, “exclusion of melanoma brain met patients from clinical research programs is no longer justified and alternate investigational approaches, possibly combining local and systemic therapies, are greatly needed for these individuals.”
So….lots of folks are on your side, NJ!!! Hopefully, archaic, irrational decisions will give way to what the data shows very soon and more patients with metastatic melanoma mets to the brain will have greater treatment options, as the data shows more and more the reality of our situation.
Yours, Celeste – chaotciallypreciselifeloveandmelanoma.blogspot.comMarch 20, 2014 at 7:31 pm #63855PhillyRedParticipant
The reason that most early phase cancer trials exclude patients with active central nervous system metastases has to do with the need for establishing a toxicity profile for the investigational agent, not based on the presumptions that it will or will not gain access to the brain/central nervous system (due to the blood-brain barrier), or whether or not it will be effective against brain mets. As mandated by the FDA, a complete toxicity profile of the investigational agent for all the organ systems of the body (including the central nervous system) must be determined before the agent is granted approval. Because central nervous system mets frequently present with a variety of neurological symptoms (depending on the size, location, and parts of the brain affected by the tumor), they can interfere with determining whether or not the investigational agent itself causes neurological adverse events, which may be serious health risks. Some early phase trials get around excluding patients with active brain mets by allowing enrollment of patients with stable brain mets (ie, causing no neurological symptoms for a certain length of time, eg, 2-3 months, or mets that have not shown growth on scans for a length of time). It depends on the pharmaceutical company, the expected toxicity profile of the particular investigational agent, and communications with the FDA about whether or not the brain mets should be allowed. Often, as the investigational agent moves into later phase trials and the company and FDA have more accumulated safety data from the earlier trials and have a better understanding of the toxicity profile, the restrictions against brain mets are relaxed, and patients with brain mets may be able to take part in the trials. With respect to the expanded access program, I think that the brain mets are being excluded because they are allowing additional patients, outside of the trial, to be able to take the drug, even though at this point in time, they don’t have extensive safety yet (as they would for a later trial), but they consider that the potential benefits of the drug for the patients outweigh the potential risks.March 21, 2014 at 1:58 am #63856Linda GParticipant Hello Catherine. My question for you with regard to the MK3475. My husbands original BRAF mutation for V600 came back negative however another genetic study revealed a mutation in a different area on the BRAF gene called BRAF L597Q (sub clonal). Does that mean he would have to try a BRAF or MEK inhibitor prior to being eligible for the Merck EAP and if so are they FDA approved or clinical trials. He is receiving IMRT and arc radiation now on face and sinus and is scheduled for 2nd Yervoy infusion on April 2. Also is this something you wait for or start registering for in advance in case the Yervoy doesn’t work Thank you.March 21, 2014 at 12:00 pm #63857 I think you have a special circumstance here, but is his melanoma considered mucosal? I hope by the time he completes the radiation and IPI, PD1 may be approved for prescription.March 21, 2014 at 12:30 pm #63858VioletaParticipant Dear Catherine,
My sis did already 10, 5 months of Zelboraf, then Ipilimumab and is now on Nivolumab.
We have also a dilemma on how to proceed regarding EAP Merck..She is still on anti PD1 trial with some signs of stability but no tumor reduction yet after 7 infusion from a total of 8. Next evaluation, at the beginning of April, it will maybe tell us more. But at the end, if she is not a responder, I think not a lot of choices are there for her, so EAP Merck can be our next hope.
What do you think? Can we to contact EAP Merck in our situation?March 21, 2014 at 12:37 pm #63859PatWParticipantPhillyRed wrote:
Because central nervous system mets frequently present with a variety of neurological symptoms (depending on the size, location, and parts of the brain affected by the tumor), they can interfere with determining whether or not the investigational agent itself causes neurological adverse events
That is interesting information about FDA rules and toxicity testing during the early phase clinical trials. Thank you for posting it. Even though this may well be the main reason why people with active brain mets are excluded, it doesn’t make any sense to me. I mean, if you develop neurological symptoms the researchers won’t know if they are cause by mets or the test drug. If you accept that, how about if you develop kidney symptoms or liver symptoms or cardiac symptoms? How do they know whether those symptoms are caused by mets or by the test drug? They do further scans and testing, that’s how. Why should neurological symptoms be any different?
I expect that toxicity testing requirements, like the blood-brain barrier issue, are both factors in eliminating people with brain mets from clinical trials. But with the new immune-based treatments currently being tested and the new less-invasive imaging technologies now available, neither of those reasons seem to make sense any more.March 21, 2014 at 6:01 pm #63860PhillyRedParticipant
To PatW and others who may have similar concerns:
In my many years of experience drafting and reviewing early phase oncology clinical trial protocols, I have never seen the issue of blood-brain barrier as a factor in determining patient eligibility for enrollment in a trial. Please note, that in early phase trials, the distribution of an investigational compound is largely unknown, especially in “first-in-human” trials. Therefore, in such trials, extensive pharmacokinetic studies to determine uptake, absorption, distribution, metabolism, and excretion will be conducted in the treated patients in these trials. With the drug disposition yet to be determined in such studies within the early phase trial, eligibility is not selected based on assumptions about where it is hypothesized the drug may be distributed. Early phase studies are focused predominantly on safety. The question of whether or not an investigational drug is able to get into the brain and shrink brain mets is basically a question concerning efficacy. And efficacy is not a primary objective in early phase trials. In early phase trials, eligibility criteria (both inclusion and exclusion) predominantly relate to safety issues.
Regarding the issue of excluding patients with active brain mets in early phase trials – the consideration is indeed safety. In patients with active brain mets, the neurological deficits are usually evolving, progressive, and non-reversible if left untreated. Such patients are often sicker than patients without such a tumor burden, and may not be expected to live long enough to complete the trial. As I mentioned previously, the presence and progression of such neurological symptoms can confound the assessment of potential neurotoxicity of the investigational agent. In evaluating adverse events (AEs) in patients treated with investigational agents, of paramount interest are “treatment-emergent” AEs, those arising during the course of treatment and related to the investigational agent. A background of pre-existing and progressing tumor-induced adverse events can mask neurological symptoms elicited by the agent. And drug-induced neurological adverse events can be very different than eg, hematological or liver function abnormalities, for which removal of the drug can reverse the adverse events (ie, anemia, low white count, elevated liver enzymes, etc). Drug-induced neurotoxicity can be unpredictable, serious, have sequelae, or be non-reversible. Case in point, review the early drug development of a non-oncology product, Tysabri, for multiple sclerosis, in which a small, but significant proportion of patients developed an unexpected, unpredicted, fatal neurotoxicity. This also led to the significant delay of approval of the drug, until a more extensive accumulation of safety data and evaluation of the reported neurotoxicity by neurologist expert consultants and the FDA who determined that if patients were selected very carefully for treatment with this drug, it could be approved because the potential benefits outweighed the considerable risks.
So, in early phase clinical trials, patient eligibility is mandated by safety concerns.March 21, 2014 at 7:03 pm #63861VioletaParticipant
Sorry to interfere, but speaking about EAP anti PD1 Merck- since this is not an early phase trial (?) to my understanding -patients with brain metastasis would be accepted, if they are treated and stable. I hope here is not the case for having concerns on neurotoxicity, since sufficient is known about drug .
In any case, thanks as well, the rationale behind exclusions/inclusions in clinical trials is interesting, although for a patient is not much consolation in it.
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