Help me! Compassionate use exceptions needed for trial drugs NOW

[Carolyns]

Hi All –
I need some advise and words of encouragement as to next steps. I am a heavily pretreated stage IV breast cancer patient. I have dealt with this disease for 20 years now 3 separate times and became Stage IV in 2006. I am a 53 year old single Mom of a 10 year old and I work full time and lead a full and productive life. So far I have responded to all of the approved and clinical trial treatments that have been offered to me for 3 to 6 months each. Eventually the disease forms resistance and I must move to the next most logical treatment. At this point there is an amazing new drug in trials T-DM1. Unfortunately, due to the fact that I am so heavily pretreated I am not eligible for this most promising trial. In my doctor’s opinion and with all of the research I have done this is the best treatment option for my situation.

Compassionate use of trial drugs for heavily pretreated late stage cancer patients is needed now! In my case T-DM 1 is the most promising drug combination on the horizon. This trial is closed to me and is not an option unless something changes fast. I am very angry about this as I feel this is a clear case of the tail wagging the dog. The primary reason I (and thousands of others like me with cancer and other diseases) are not eligible for this treatment is that there is no compassionate care usage approved for trials / trial drugs. As it stands presently, the drug companies must include outcomes of heavily pretreated patient populations like me in the trial results. The feeling is that this heavily treated population might not respond as well as people with less treatments. If this happened it could hurt the chances of these trial drugs getting beyond the trial phase. I would never want this to happen, but…

This drug combination has shown amazing promise and all of the experts in the breast cancer community agree. Do you have any ideas of ways to get the spotlight shown on this issue?

All we need is for the FDA to allow for Compassionate use of trial drugs to heavily pretreated patient populations without inclusion in trial results. We do not wish to slow down or negatively impact trial results. What we would need and deserve is a chance to benefit from these drugs rather than die while waiting for approval. There is no logical reason that we should not have access to this drug combo. Compassionate use of trial drugs for late stage patients needs to be pushed so that people like me can get the best treatment while there is still time.

Thoughts?
Carolyn

[StephN]

Dear Carolyn -
Have you contacted a group called Breast Cancer Action (think that is their name)? There is a group that is quite rowdy and makes a lot of noise on issues such as this. See what they are doing.

When I saw my med onc on Wed. she mentioned that my center is part of the T-DM1 trial and that it filled so fast nationally, she had a line of patients in the approval process that were cut off and remain that way until the drug is fast tracked and approved. She is pleased with how her patients are doing and said, "we need this one approved as fast as humanly possible."

Maybe someone else has further ideas on activist groups that may help you.

[Joe]

Here is a trial that you may be eligable for:

T-DM1 Trial

You may also wish to investigate Neratinib which also has had good results for patients whta herceptin failed to help:

Current Neratinib Trials

About Neratinib:
12 / 12 / 2008



Wyeth Announces Positive Data from Phase 2 Study of Neratinib in Advanced HER-2-Positive Breast Cancer

- Global Phase 3 Program Expected to Begin in December -
Collegeville, Pa., December 12, 2008 – Wyeth Pharmaceuticals, a division of Wyeth (NYSE: WYE), today announced data from an open-label phase 2 clinical trial of neratinib (HKI-272) in women with advanced HER-2-positive breast cancer. These data suggest that neratinib has antitumor activity in patients with advanced breast cancer positive for the ErbB-2 receptor (also known as HER-2 or Neu). These data were presented today during an oral session at the CTRC-AACR San Antonio Breast Cancer Symposium.
Neratinib is an investigational orally-administered potent and irreversible dual inhibitor of the HER-2 and EGFR kinases. Wyeth expects to initiate the first study in a global phase 3 program for neratinib in advanced HER-2-positive breast cancer later this month.
"Neratinib demonstrated activity against trastuzumab-resistant and trastuzumab-naive HER-2-positive breast cancer," said Harold Burstein, M.D., Ph.D., a study lead investigator at Dana-Farber Cancer Institute in Boston. "These results warrant ongoing study to see whether neratinib will fit into our armamentarium of anti-HER2 drugs."
The phase 2 study evaluated the safety and efficacy of a daily 240 mg oral dose of neratinib in 136 women diagnosed with ErbB-2-positive locally advanced or metastatic breast cancer (stage IIIB, IIIC or IV). The primary end point of the open-label, two-arm study was the 16-week progression-free survival (PFS) rate. Secondary end points included safety, objective response rate (complete and partial responses) and clinical benefit rate (objective response plus stable disease).
Patients were assigned to one of two study arms based on prior treatment with trastuzumab (Herceptin®, Genentech), the standard of care for the treatment of advanced ErbB-2-positive breast cancer. Women enrolled in arm A (n=66) had either previously received at least six weeks of standard trastuzumab treatment or had experienced disease progression during or following trastuzumab-containing adjuvant therapy. Women in arm B (n=70) received no prior treatment with any ErbB-2-targeted therapy, including trastuzumab.
The efficacy analysis included 127 evaluable patients, 61 in arm A and 66 in arm B. In patients who were previously treated with trastuzumab (arm A), the 16-week PFS rate was 60 percent, and the median PFS was 23 weeks, as evaluated by independent assessment. The objective response rate was 26 percent, and the clinical benefit rate was 36 percent. In patients who had not received trastuzumab treatment (arm B), the 16-week PFS rate was 77 percent, and the median PFS was 40 weeks by independent assessment. The objective response rate was 56 percent, and the clinical benefit rate was 68 percent.
Adverse events of any grade occurring in more than 15 percent of study patients included diarrhea, nausea, vomiting, fatigue, anorexia, abdominal pain, headache and rash. Diarrhea was the most common toxicity and was observed in 93 percent of patients. Diarrhea was also the most significant grade 3 or 4 adverse event, occurring in 21 percent of patients. Diarrhea was reversible and generally manageable by medication, treatment interruption or dose reduction. One patient discontinued treatment due to diarrhea.
“Wyeth’s exploration of neratinib demonstrates our ongoing commitment to research of promising investigational therapies in areas of significant unmet medical need, including oncology and women’s health,” says Gary L. Stiles, M.D., Chief Medical Officer, Wyeth. “These phase 2 data provide important insight into the potential clinical utility of neratinib in HER2-positive breast cancer.”
The American Cancer Society estimates more than 182,000 women in the United States will be diagnosed with breast cancer in 2008, and more than 40,000 will die from the disease. The HER-2 receptor is over expressed in 25 percent to 30 percent of breast cancer patients.



Warmest Regards
Joe

[Jean]

I would like to know how long the TDM1 trial has been on going?

This may be a dumb question so forgive me....
but like herceptin was off label to many of us before it was approved by FDA for early stage bc...can the TDM1
be available off label?

[StephN]

Re - off label t-DM1.

My information is that it is not allowed off label at this point. I also do not believe that Herceptin was given off label until it was approved by the FDA in 1998. It was approved then for stage IV, but given in other circumstances.

[Barbara H.]

I have been on the T-DM1 trial since September 07. I believe this drug has been in trials for about three years. I am currently on the weekly trial. I hope that it is approved soon, but unfortunately these drugs take a long time to be approved. I wish it were approved so that I could take a break from it for a few weeks.

I feel your frustration. Herceptin was available in 98 when I was first diagnosed. However, it was not available to me. I feel that Herceptin could have made a difference in keeping me from progessing to stage 4. When I recurred it was in my lungs, brain, liver, skin, and lymph nodes though out my body. After brain surgery I was only given Herceptin, and I was NED within two months. Unfortunately, it did spread to the bones 1 1/2 years later. I did do Navelbine for about 9 months and then took a vacation from Chemo until I went on the T-DM1 trial. It is still working for me.
I do hope that T-DM1 becomes more available soon.
Best regards,
Barbara H.

[Jean]

Steph,
I had herceptin prior to FDA approval for early stage
off label...would it be considered similiar to have the
TDM1? I went on line to do some checking....
but I am not finding anything yet.

[Jean]

Carolyns,
Have you contacted Genentech and asked them when they think the drug will be approved. I know that they are fast tracking it. Are there any dates out there ?

Jean

[chrisy]

Jean,

You being able to receive herceptin off label is different. herceptin WAS an FDA approved drug, but it was approved for a different indication (Stage IV only). So getting a drug off label means you receive it for something other than what is has been approved for.

T DM1 is not approved yet at all. So currently the only way to get access to it is via a trial. Until/unless it is offered on a compassionate use basis for people who cannot qualify for trials.

Carolyn, I couldn't agree MORE that they should allow more drugs to be available to people who could benefit and are running out of options. It makes me angry as well. The FDA seems to be going the opposite direction from the way they need to go...

[Carolyns]

Thank you for your replies.

I went to a meeting tonight and estimates are that it will be approved by Dec. 2010. My doctor said that the only way things will change is when the FDA allows for compassionate use of trial drugs to late stage patients. Tonight the speaker at Gilda's club said that over 100 applicants were turned away from the last TDM1 trial. These were all late stage heavily pretreated women with limited options. It seems criminal to me and I know this is not the intent. This must change - it does not make any sense at all. I will be forced to take a drug with more harsh side effects and pray that I make it until TDM1 is approved. I am still angry.

[Jean]

Carolyns,
I am angry with you....

Chrisy...
Thank you for clarity. Wish we could do something.
This is very upsetting. I understand the cautious behavior on the part of the FDA...but
if the TDM1 is showing such great results why does the FDA refuse compassionate use?


jean

[BarbM]

I am very interested in the drug, too. Guess I wouldn't be considered heavily pretreated yet, but as quickly as I am going through drugs, it won't be long. I am dealing with some harsh side effects of Doxil...can't wait for T-DM1! Can't come soon enough...maybe, if we all storm the front doors of the FDA it will get someone's attention!

[Lani]

ASCO 2009: Should Experimental Cancer Therapies Be Available Outside Clinical Trials?

June 18, 2009 — Patients with life-threatening illnesses have the right to refuse treatment, but do they also have the right to treatment with experimental drugs if no approved treatments exist?

These questions were addressed during a session here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting.

"We know that there is strong demand for experimental therapy from patients," said Jeffrey Peppercorn, MD, MPH, assistant professor of medicine at Duke University in Durham, North Carolina. Oncologists need to understand the arguments for and against wider access to these agents, he added.

Investigational cancer therapies being tested in clinical trials can be available outside of trials or "off-protocol," and the extent to which patients should have access to these agents is a hotly contested issue. The demand for and the availability of off-protocol therapies, combined with differences in practice and attitudes among oncologists, demonstrates a need for wider awareness and discussion of this issue in the oncology community, Dr. Peppercorn explained.

Under most circumstances, treatment with an unproven agent outside the auspices of a clinical trial cannot be justified on clinical or ethical grounds. However, the challenges and ethics of off-protocol therapy have to be addressed, according to Dr. Peppercorn.

We know from many studies and common sense that many patients come to us seeking clinical trials for their own needs.
One of the concerns is that increased access to off-protocol treatment will lead to slower accrual in clinical trials, which are urgently needed in many oncology settings to improve outcomes. "While patients participate in trials through altruism and to help us improve care for future patients, we know from many studies and common sense that many patients come to us seeking clinical trials for their own needs," said Dr. Peppercorn. He pointed out that the same factors that drive the need for cancer research also drive patients to seek out promising experimental therapies.

Off-protocol therapy also raises issues regarding access to novel interventions by patients of different socioeconomic backgrounds, patient safety, and diversion of focus and resources.

Patient-Advocate Perspective

Ellen L. Stovall, acting president and CEO of the National Coalition for Cancer Survivorship, noted that many patient advocates are ardent supporters of clinical trials. "We have a long history of clinical-trials advocacy, and that has been a very high priority for our organization and many others in the advocacy community," she told the meeting.

Very few patients are enrolled in clinical trials, which creates a terrible dilemma.
"We feel that clinical trials are really the way to go in order to find out what works and what doesn't work in cancer care before exposing thousands of patients to these drugs. But we also know that very few patients are enrolled in clinical trials, which creates a terrible dilemma for us and for the investigators," she said.

This creates a conundrum, she contended. "How do we support both clinical trials as a standard of care and ready access to unapproved drugs outside clinical trials without hopeless inconsistency and lack of credibility for advocacy?"

Patient demand for access to experimental therapies drew media attention when the advocacy group Abigail Alliance filed a lawsuit against the US Food and Drug Administration (FDA), asserting that cancer patients with no other treatment options who were ineligible for clinical trials had a "constitutional right" to experimental therapies that had completed phase 1 trials. Although the court ruled in favor of the Abigail Alliance in 2006, an appeals court reversed that decision the following year. The US Supreme Court declined to hear the case, which effectively ended the appeals process, leaving the existing FDA regulations intact.

But there is currently very little middle ground for patients between viewing a single-use investigational new drug as a constitutional right and randomized clinical trials. "Some advocates have agreed to individual access outside of trials under certain circumstances, such as when all standard treatment options have been exhausted and patients do not meet the criteria for a clinical trial," said Ms. Stovall.

Ideally, any expanded access should be part of an overall clinical development plan, and patients participating in expanded-access plans should primarily be those ineligible for clinical trials. "Expanded-access plans should provide a framework for data collection and reporting that requires compliance for collection and reporting by sponsors," she added.

Variation in Practice Among Oncologists

A pressing issue for the oncologist is what to do when a patient requests an experimental drug outside of a clinical trial. Another issue to ponder, Dr. Peppercorn pointed out, is whether there is "a clear rationale for withholding an experimental therapy outside of a trial, when we are prepared to use it to treat a patient within a trial."

Dr. Peppercorn and colleagues conducted a survey to evaluate the practices and attitudes among American oncologists and to gain a better understanding of how oncologists deal with requests for experimental therapies (J Clin Oncol. 2008;26:5994-6000). Of 500 oncologists randomly selected from the ASCO database, 31% responded. "That's a good response rate for doctors," he noted, "but it does introduce some bias into our results."

The vast majority of respondents (93%) reported discussing experimental therapies with patients, and 81% stated they had prescribed them. Within this group, 66% reported prescribing investigational treatments at least once a year, and 12% said they prescribed an off-protocol therapy once a month or more frequently.

"We found that this is happening in the real world and most often in the academic environment," said Dr. Peppercorn. "I should add that most of the physicians felt that patients should be discouraged from doing experimental therapy outside of clinical trials."

However, the most interesting part of the survey was the responses from oncologists when specifically asked about case scenarios that were drawn from then-ongoing clinical trials. There was lack of consensus, Dr. Peppercorn noted. An example was the use of adjuvant trastuzumab, which 41% stated they would provide to patients outside of the ongoing trial and 59% stated they would not.

"We found a split among oncologists," he said, "and it didn't really vary by practice setting, but I think this was significant."

Implications of Off-Protocol Use

Dr. Peppercorn pointed out that the majority of recent oncology trials involve experimental regimens that are available outside of a clinical-trial setting. In a study presented during an Education Session at the ASCO meeting, Dr. Peppercorn and colleagues evaluated the availability of off-protocol therapies outside of clinical trials, and the potential impact on trial accrual, patient safety, and access to care.

They identified 172 phase 3 randomized controlled studies over a 2-year period ending April 17, 2008. The majority of trials (108; 63%) evaluated drugs that were available off-protocol at the beginning of the trial, and an additional 19 (11%) evaluated drugs that became available during the study period. More than half of these (64; 55%) were available because they had FDA approval for the same cancer in a different setting, 40 (35%) had approval for a different cancer, and 12 (10%) had approval for a noncancer indication.

The studies conducted with experimental therapies that were available outside the confines of the trial had a slower time to completion than trials with drugs that were unavailable (48 vs 26 months; P = .04). There was also a trend toward slower accrual (14.0 vs 40.7 patients/month; P = .06).

"We found that for the majority of these studies, the experimental arm had at least 1 new grade 3 or 4 toxicity, which highlights the importance of testing these drugs in trials," he said. "There were several studies where the experimental arm was worse than standard care."

These findings show that there is a need for discussion and guidelines within the oncology community, Dr. Peppercorn said. "I know as much as we are all fans of clinical trials and evidence-based medicine, as doctors, we are going to come up against this," he said.

The Abigail Alliance case did not end the legal battles for access, Dr. Peppercorn pointed out. "There are still pending legislative efforts to move this forward, so this is not the last that we'll hear of it."

"I think the Abigail Alliance is part of the beginning of the discussion and not the end, and I hope we continue to think through and work on these issues together," he added.

Access to Medical Devices

At the same, ASCO session moderator Joel Tepper, MD, a Hector MacLean Distinguished Professor of Radiation Oncology at the University of North Carolina/Lineberger Comprehensive Cancer Center in Chapel Hill, addressed a related issue — that of medical devices. There are ethical and practical issues involved with the use and approval of medical devices, he explained, but they are not well addressed by regulatory bodies.

"They really are, in many ways, inherently different than pharmaceuticals," said Dr. Tepper. "Medical devices all provide a critical function in medical care, but does an improved scalpel need a phase 3 randomized trial?"

The regulatory hurdle for devices is different than for pharmaceuticals; they basically have to perform the function for which they were designed and be able to do it safely. "But there is no real definition of efficacy," he noted. "And relatively few devices are really different from what came before. The critical issue is that the biology remains the same."

In some cases, the technology is very different from what is conventionally used. This includes robotic surgery, laparoscopic surgery, the harmonic scalpel, and proton radiation therapy. Even though the technology is dramatically different, the biology is the same, Dr. Tepper said.

One example is when improvements are made to x-ray delivery systems. Although new technology enhances the accuracy of the system, it still produces the same type of radiation beam, so it doesn't change the basics. The same is true for Port-a-Caths and infusion pumps — they deliver the same drug, but in a different way, Dr. Tepper said.

"In my opinion, randomized trials are ethically necessary when the new modality is, in some sense, inherently different," he said. "New biological therapy is, in virtually all situations, experimental."

But the dividing lines are very murky to say the least, Dr. Tepper added.

New technologies can be considered experimental if it is unclear whether the new approach does the same thing as the older technology and it is reasonable to assume that there can be alterations in outcomes. Dr. Tepper cited the example of laparoscopic vs open surgery: Do the surgeons perform the same operation?

The primary question, he said, is whether randomized trials need to be performed in the absence of any change in biology. He pointed out that randomized trials comparing laparoscopic and conventional techniques in colorectal cancer surgery have been conducted, but wondered what the end point should be.

"The primary reason for randomized controlled trials is to protect patients, and if the risk is low, I believe that you don't need them because you are not protecting anyone," he said.

As with new pharmaceutical agents, it is unclear whether new devices should be available to the patient outside of clinical trials, he noted.

Dr. Peppercorn reports serving in a consultancy/advisory role for AstraZeneca and Genentech; receiving honoraria from AstraZeneca, Eli Lilly, Genentech, and Pfizer; and receiving research funding from Genentech and Merck. Dr. Tepper and Ms. Stovall have disclosed no relevant financial relationships..

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Education Session, presented May 30, 2009; Abstract 6539, presented June 1, 2009.

[schoonder]

Possibly a request for compassionate use of t-dm1 made by your oncologist directed to company might result in obtaining further information as to how to proceed.

"Genentech® Access to Care Foundation Genentech is committed to helping patients have access to our therapies. For those eligible patients in the United States who do not have insurance coverage or who cannot afford their out-of-pocket co-pay costs, the company provides several support options through the Genentech Access Solutions program. Since 1985, when our first product was approved, Genentech has donated approximately $1.3 billion in free medicine to uninsured patients through the Genentech® Access to Care Foundation (GATCF) and other charitable programs.
For consideration of eligibility for resources from the Genentech® Access to Care Foundation, the patient must meet eligibility criteria including income restrictions. Please direct requests for applications forms and more specific information on eligibility to:

Genentech Access to Care Foundation
1 DNA Way, MS #13A
South San Francisco, CA 94080
(800) 530-3083
FAX: (650) 225-1366

[Carolyns]

THANK YOU, THANK YOU!!!

I must continue this fight on Monday as my real job is too demanding today to spend more than a minute on this today. As far as I can tell TDM1 is the most logical, safest next step for me and I am determined to fight as loud and strong as I can to get it while I have the physical strength to do so. I will try the process suggested here first and greatly appreciate the suggestions and support. I am not alone here as I now know that there were at least 100 other women physically turned away from the trial after they applied because it filled up so fast and those were only the women who got there first and fast. This is just wrong.

Carolyn

[Carolyns]

Dying Patients Seek Trial Drug Access


Families of Terminal Patients Urge Better Access to Experimental Drug

http://abcnews.go.com/WNT/Story?id=130922&page=1

[schoonder]

I don’t know if Dr. Rugo, a t-dm1 investigator at UCSF has made any progress with FDA petition for drug’s “compassionate use”. I do know that one of her conditions has been met, t-dm1 is presently being evaluated in a phase III setting. Here’s an excerpt from article in Cure magazine that quoted her intent:

“In terms of potential treatments for metastatic disease, “There is just a whole explosion of drugs out there,” Hope Rugo, MD, of the University of California at San Francisco, said in an interview with CURE.
One of those drugs is trastuzumab-DM1 (T-DM1). According to data from a phase II trial presented by Svetislava Vukelja, MD, of Tyler Cancer Center, T-DM1 has anti-tumor activity in patients with previously treated HER2-positive metastatic breast cancer, including activity in patients who have been pretreated with trastuzumab or lapatinib.
Rugo was one of the investigators in the trial, and she explained, in an interview with CURE, that T-DM1 is Herceptin linked to a chemotherapy drug that acts as a toxin. It works by taking advantage of the fact that the HER2 receptor binds to Herceptin and brings it into the cell. “So if the Herceptin has a toxin attached to it, you are delivering the toxic payload straight to the cancer cell. It’s called a smart-bomb approach.” Rugo said T-DM1 has been so effective in treating patients whose disease has progressed despite treatment, her team is looking into the possibility of petitioning the Food and Drug Administration to allow compassionate use of the drug after it enters phase III trials.
Rugo added that oncologists are exploring whether existing drugs could be used in new ways. “Maybe in the future, when we’re combining biologic agents, we can combine oral agents with an antibody. That’s very encouraging, because these are drugs that are already out there,” she concluded.”

And yes, life is much too precious to have it abridged by obvious shortcomings in expediency of how today’s new generation of drugs are made available to critically ill patients.
Possibly following link will help you on your journey to obtain this drug.
http://www.canceractionnow.org/living/cat_compassionate_use_and_expanded_access.php

[Barbara H.]

Hi Carolyn,
Irene from Tampa was heavily treated and she was eventually able to get on a T-DM1 trial. Perhaps there will be a trial available for heavily treated patients before the drug is approved. They already have evidence that it works in heavily treated patients. I would have your oncologist contact Genentech.
Best,
Barbara

[erica35]

Sounds like there are a number of advocacy organizations to go through. I am certain that we could start a letter writing campaign to Genetech asking them to start a new trial for heavily pretreated her2+ metastatic breast cancer. If this is needed I am sure we can whip up the masses to make sure Genetech and the FDA hears a loud voice. This worked for HIV antivirals. Why not in this case?

[Joe]

Genentech is well aware of this situation and the problem was addressed by them at a meeting between us and them at ASCO and here is a summary of our meeting:

T-DM1 Expanded Access Program

We have had several posts from members who were disappointed that they were
ineligible for trastuzmab-DM1 (T-DM1) clinical trials. We met with several
representatives of Genentech while at ASCO to discuss your concerns.

Here is some information about T-DM1 trials that may be helpful:

The current T-DM1 phase III trial is open to enrollment now for patients who have had
no prior treatment with Tykerb (Lapatinib) and / or Xeloda (Capecitabine). The two
Phase II trials that have been fully enrolled are no longer available for patients.
However, Genentech is committed to opening new trials to address patients’ needs;
another Phase II trial of T-DM1 is due to open within the month. In addition, Genentech
has recently opened a Phase I/II trial of T-DM1 combined with Pertuzumab that will
enroll up to 60 patients:

http://clinicaltrials.gov/ct2/show/NCT00875979?term=pertuzumab+TDM1&
recr=Open&rank=1

Each trial will have slightly different inclusion / exclusion criteria, but neither have
restrictions on what prior treatment(s) patients may have received provided they have
not been given T-DM1 or T-DM1 and Pertuzumab.

During our conversation, it was clear that Genentech understands your frustrations. We
discussed the following possible steps, and will keep you posted as we learn more.

1. Expanded Access – We all agreed that it is premature to offer T-DM1 for
compassionate use at this time as the Phase III trial has only recently opened for
recruitment and the results from the second phase II trial are not yet available.
However Genentech will consider launching an Expanded Access Program after
it accumulates sufficient data warranting this.

Additional Clinical Trials –Genentech will provide us with the location of new trials as
they are opened for recruitment.


Note:
There was a delay in posting this as I had agreed to allow Genentech's legal department to approve the post.

Regards
Joe