Ruminations 10: Not So Glad Tidings

Rumination 10: Not So Glad Tidings.

by Thomas Vogl

December 15, 2007

The good news is that I feel just as hale and hearty as I did when I wrote Rumination 9 in late September and that there are a number of options now open to me that were not available a year ago. That is how fast melanoma research is moving.

The bad news is that in the repeat scans done November 28th, there is evidence of melanoma in two new places my liver. So the issue is what, if anything, to do now. In advance of meeting with Dr. Hodi (yes, Dr. Norris persuaded me to try again, hopefully with far better communication) I reviewed the literature and the available clinical trials.

Two immediately relevant new items in the literature caught my attention because they may provide clues as to how and why the immune system is, or is not, responding adequately. A recent review article, The Genome and Epigenome of Malignant Melanoma [C. Dahl and P. Guldberg, APMIS115: 1161 (2007)] and an item about Dacarbazine (below). Among interesting points in this review article is the fact that the tumor suppressor PTEN, a gene that is often mutated by cancers, is often inactivated in prostrate cancer (which I had) and in 30-40% of melanomas.  They also report that aberrations in the Wnt signaling pathway, particularly APC, is related to colonic polyps (which I have and which run in my paternal family) and methylation of the APC promoter 1A is present in about 15% of melanomas. I will be most interested to find out from Dr. Hodi whether the science is far enough along to have these observations influence choice of therapeutic modalities. The paper quotes Miller et al., [N. Engl. J. Med., 355: 51 (2006)] in reporting a median survival of six months (no standard deviation given), which I have already beaten by a factor of two.

I have recently developed a possibly relevant hypothesis: For the past two years I have been annoyed by an unexplained skin rash that waxes and wanes. It last bothered me in Italy in June and was quiescent thereafter until November. In that interval an infection developed in the root of the molar holding my prosthesis, so the dentist and I are trying to save the tooth, rather than extract it. I have noticed that when the rash is at its worst, the tooth is at its best, and vice versa. The hypothesis is that the rash is a manifestation of a hyperactive immune system that is endeavoring to keep the melanoma in check (and fortuitously controls the tooth infection) and is the underlying cause of the remission this Spring.  Unfortunately, I have no idea how to test my hypothesis. Any suggestions, anyone?

As those who have known me over the decades know, my track record for hypotheses that have been validated is pretty darn good (I'm really not trying to blow my own horn, it's just historical, and possibly relevant, fact). When I combine this hypothesis, hunch if you will, with the fact that I am adamant about maintaining as rectangular survival curve as can possibly be achieved, the possible therapeutic interventions are limited to relatively benign drugs that give my immune system a good kick. All the standard therapeutic modalities have serious side effects and do not increase life expectancy. Ditto for some of the newer modalities such as Dacarbazine [P. Lui et al, Cancer Treatment Reviews, doi:10.1016/j.ctrv.2007.06.004].

None the less, I am heartened by the number of, to me, acceptable clinical trials, not available a year ago, that are now on the books or imminent. (For those of you interested in reviewing all of them: http://clinicaltrials.gov/ct2/results?term=melanoma.)

In order of my preference, based on trials I knew about as of December 8, and what I knew about them, the three clinical trials in which I would consider participating are:

The Syntra trial of STA-4783 (Elescomol). Not yet FDA approved, but supposedly nearly there.  I would be willing to wait a few weeks for it since it appears to be a very promising therapy.

NCT00094653 "MDX-010 Antibody, MDX-1379 Melanoma Vaccine, or MDX010/MDX-1379 Combination Treatment ..."  I find this one very attractive because each arm is a promising approach; it requires me to be HLA-A*02901 positive, and I have no idea whether I am or not -- a lab test will answer that question. (The HLA histocompatibility complex acts as a ligand for some receptors (CD94/NKG2) on the surface of natural killer cells and for a subset of T cells that (hopefully) attack the melanoma cells. Its presence is needed to make the vaccine component of the trial effective.)

NCT00495066 "Compassionate Use Trial for Unresectable Melanoma with Ipilimumab (MXP-010).

Unfortunately, most clinical trials have become very weird beasts.  I was planning to write a diatribe on the subject in this Rumination, but the 'Perspective' in the New England Journal of Medicine beat me to it (Hurray!) [NEJM 357:2219 (November 29, 2007) http://content.nejm.org/cgi/content/full/357/22/2219 ]. What fascinates me about this 'Perspective' is that all the benefits and pitfalls (see table from that paper, below) that were predicted when we discussed these issues in the 1970's when I was at the National Academy of Sciences have come to pass. What was not anticipated, and is the true horror story of the situation, is how many of these studies, funded by the drug companies, have turned into bad science driven by marketing considerations. From the Perspective (emphasis added):

" Although the traditional means of assessing drugs, the randomized, controlled trial, is the rightfully enshrined standard for determining efficacy, such studies often have important drawbacks (see Table): limited size, making it difficult to detect uncommon adverse events; short duration, even for drugs designed to be taken for a lifetime; frequent reliance on placebos as the comparator, limiting clinical relevance; termination after a surrogate end point is achieved, without measurement of real clinical effects; and underrepresentation of patients with complex health problems, especially the elderly. Some of these limitations result from lax study protocols that are proposed by manufacturers and are too readily accepted by the FDA. But others are inherent in the randomized, controlled study design. No trial could ever be large enough to gather enough data to quantify the risks of all uncommon side effects, and studies lasting long enough to document all clinical outcomes would be impractical if they required many years of follow-up before approval could be granted. In addition, since the FDA generally doesn't require head-to-head comparisons of similar drugs, preapproval trials are unlikely to provide the comparative data that physicians, patients, and payers need. Improvement in study designs could address some of these problems, but many are hardwired into the nature of randomized, controlled trials."

Strengths and Weaknesses of Randomized Controlled Trials and Observational Studies of Medications.

You do understand that the diatribe that I would have written would not be as gentle as NEJM's, because I feel that any experiment that does not allow for an equally useful amount of information to be extracted from all possible outcomes is a badly designed experiment. When two drug companies run trials on different drugs against the same disease and end up competing on the basis of "my drug ameliorated 9% of the cases" (whereas the other company's only ameliorated 7%) without any effort to determine whether the populations (7% and 9%) are the same or different, nor any effort to determine what differentiates the 7% (or 9%) from the rest of the tested population, are abominably bad science, but make sense from the marketeer's perspective. The Gleevec (Imatinib) study (for which my melanoma does not have the right genetic characteristics) appears to be a partial exception from this general attitude as apparently does the NCT00094653 Combination Treatment study that requires HLA-A*02901 to be present. At least they make an effort to prescreen the test population for features of known relevance to the action of the drug being tested. Note that in both these studies these restrictions are, as the mathematicians say, necessary but not sufficient. That is, the drugs are known not to work unless these conditions are met, but that does not mean that they will work if they are.

The foregoing was written on Saturday, December 8.  What follows was written on December 14th.

I based my choices in part on an announcement that appeared on June 6, 2007:

"Medarex, Inc. (Nasdaq: MEDX) and Bristol-Myers Squibb Company (NYSE: BMY) today presented results from multiple clinical studies of ipilimumab (MDX-010), an investigational immunotherapy, for patients with advanced melanoma. The results demonstrated an anti-tumor response in some patients with advanced melanoma either as a monotherapy or in combination with other therapies. The results of the monotherapy study showed that 19% of patients (17/88) with advanced melanoma treated with ipilimumab experienced control of their disease, including tumor shrinkage and stabilization. The second presentation showed that complete or partial response was achieved in 13% of patients (46/356) with advanced melanoma when treated with ipilimumab alone or in combination with traditional chemotherapy (i.e., dacarbazine), interleukin-2, or a gp100 peptide vaccine. The results of this analysis also indicated that treatment with ipilimumab may take 12 weeks or longer to induce a response. These findings were presented at the American Society of Clinical Oncology's 2007 Annual Meeting in Chicago.

[clip]

In the cohort of 23 patients who were treated at 10 mg/kg, disease control was achieved in 39% (9/23), which lasted six months or longer in nearly all patients (8/9)." [clip]

On Monday, there was a big flap with many stories in the press:

Mon Dec 10, 5:41 PM ET

NEW YORK (Reuters) - Bristol-Myers Squibb Co and Medarex Inc on Monday reported mixed top-line results from three key studies of their experimental drug for advanced melanoma, but said the data were strong enough to seek approval from U.S. health regulators.

One of the three studies of the drug, ipilimumab, failed to meet its primary goal, which was to rule out a best objective response rate of less than 10 percent, the companies said.

Why the big flap?  Because if it works in less than 10% of the people with metastatic melanoma, the market potential and therefore the profit is limited. The headlines:

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*MEDX hits 52-week low at 10.16

Wednesday, December 12, 2007; Posted: 09:42 AM

RTTNews) - Shares of Medarex Inc. (MEDX | charts | news | PowerRating) dropped almost 21% on Tuesday after the company revealed mixed results from three drug trials. The stock gapped open lower, drifting further throughout the morning. MEDX closed at $10.56, down $2.79.

Wednesday's slide moved the stock below support to a new 52-week low.

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The real issue, it seems to me, is not on how many patients a drug works, but to devise methods of determining for which patients it will work. Yet in none of the clinical trial descriptions in the official database, nor in the consent forms I have seen for the two studies, is there any mention of any tests to try to discriminate between those trial participants for whom the regimen works from those for whom it does not. Clearly, nobody knows. Yet I find it hard to believe that no testable hypotheses exist. See Chin et. al. [Malignant melanoma: genetics and therapeutics in the genomic era, Genes & Development 20:2149 (2006) on line at www.genesdev.org/cgi/doi/10.1101/gad.1437206] and Fecher et, al. [Toward a Molecular Classification of Melanoma, J. Clinical Oncology 26:1606 (2007)].

Why does the FDA not insist on their inclusion in all clinical trials? How do they know whether the 20% of patients on which drug A works is the same or a different population that the 18% on which drug B works? If they do not know, nor attempt to find out, is that not inexcusably sloppy science?

Sufficient onto each day is the diatribe thereof. Enough.

On Wednesday, December 12 I met with Dr. Hodi. The meeting was productive, calm, and businesslike. I did not expect warmth and relevant conversation since I knew that was too much to hope for, but it was by far the least disturbing meeting with him so far.  The conclusions from the visit are easy to summarize. There are three possible drug trials to consider:

The compassionate use trial of Ipilimumab that will be available locally by February and is currently available at other locations, including Yale.

The Elescomol (Syntra's STA-4783) trial for which no starting date estimates are available and which is a drug with a totally different mode of action from any of the others; everyone is optimistic about it, but it is definitely a shot in the dark with respect to any particular case.

Several companies are working on a new class of drugs, small molecule tyrosine kinase inhibitors, that inhibit c-Met. Of particular potential interest to me is the research being done at the University of Chicago by Puri et. al., [c-Met is a potentially new therapeutic target in the treatment of human melanoma. Clin. Cancer Res., 13:2246 (2007)]. Not having ever been involved in immunology, my understanding of the pathways involved is superficial and I am just beginning to learn about them; hence the following summary is subject to revision and I apologize in advance for my misunderstandings and mistakes. c-Met (Mesenchymal epithelial transition factor) is a proto-oncogene that is a tyrosine kinase membrane receptor for hepatocyte growth factor/scatter factor (HGF/SF) that is involved in melanocyte growth, and melanoma development and adhesion. So the inhibition of c-Met and HGF which is involved in both the proliferation and attachment of melanoma cells has been a target in melanoma research. Puri et. al., have been investigating two drugs, a synthetic small molecular weight tyrosine kinase inhibitor, SU11274, and a siRNA ('small Interfering RNA') that serve to interfere with the expression of specific genes. This approach has been very successful in laboratory experiments and is now ready for clinical trial in a Phase I study for which I may be eligible. Because my metastases are in the liver, this approach may make theoretical sense. I have no idea, at present, what the side effects might be, particularly potential long term side effects. That certainly will influence any decision.

I am still trying to investigate what interaction, if any, exists between the c-Met and the PTEN pathways. Stay tuned.

What I will actually do will be decided when I see Dr. Hodi again late in January.

The other news is that since I returned from Missouri, despite my efforts and efforts on my behalf, I was unable to locate a lab to run the plasma separation protocol for me, either on the Cape or in Boston. So, with the help of Bruce Kristal (thanks, Bruce) I bought a second hand centrifuge – costs no more than one trip to Missouri – and I'll go back to Missouri in January to observe/learn the protocol. More on that in January.

In the meantime, I look forward to our annual winter solstice party (December 23, noon to eight). You are all invited.