Clinical Trials el pt

Clinical Trial Updates - PCR vs FCR

Date: January 17, 2024

by Chaya Venkat

Comparing Apples to Kumquats; One Small Victory

All too often we get to hear about clinical trials when they are first announced, then the hoopla dies down and we move on to the next miracle of the month drug or therapy combination. I am going to make a serious effort to break that practice. This short article gives you updates on two important clinical trials that we have discussed before.

Comparing FCR versus PCR

Last weekend P. C. and I spent a couple of days at Scottsdale, attending the third annual Mayo symposium on hematological cancers. This is a continuing medical education (CME) seminar for local hem/oncs. A real hardship for us, given the weather was a sunny 70 F, the skies were clear cobalt blue and the seminar was held at the ritzy Scottsdale Camelback Inn. It is a tough life, but someone has to live it, right? Kidding aside, it was very educational and I learnt a lot. It is not often I get a chance to rub elbows with experts such as Dr. Neil Kay and Dr. John Byrd, and I thank Mayo Clinic for giving me the opportunity.

The reason I brought up the seminar is that one of the talks discussed PCR vs FCR comparison.

The high response rates and high percentage of "CR" and "pcr negative" responses obtained by FCR therapy (fludarabine, cyclophosphamide and Rituxan) pioneered by M. D. Anderson has generated a great deal of interest. However, there has also been concern regarding the toxicity, immune suppression, opportunistic infections and potential for secondary cancers associated with this heavy-duty combination. In fact, one of the clinical trials we reviewed recently (FCR Lite) addresses that very question: this new approach tries to maximize the response statistics (by virtue of increasing the amount of Rituxan used), while reducing the amount of fludarabine and cyclophosphamide used. Only time will tell if this new dosage design will get us a better bang for the buck.

The "PCR" combination offered as a clinical trial at Ohio State and Mayo Clinic is another effort to reduce the toxicity without losing the high response rates. In the PCR regimen fludarabine is replaced by its sister purine analog pentostatin, hence the "P" in PCR. These researchers feel that pentostatin may cause less immune suppression than fludarabine, and therefore may be kinder and gentler than the FRC regimen. The hope is that the reduced immune suppression will translate into fewer infections, hospitalizations, etc.

How do we judge which approach is better? A true one-on-one comparison of the two approaches can only be done in the context of a well conducted (preferably multi-center) clinical trial where patients are randomly assigned to get either PCR or FCR, and then the results obtained for the two groups are compared down the road. But such large size, phase-3, multi-center, double arm clinical trials are expensive to conduct, as well as time consuming. All too often these days, researchers are sliding by on single institution phase-2 trials, without even a built in control group. This leaves all sorts of room for possible recruitment and institutional bias. You know the old saying, beauty is in the eye of the beholder. We are more likely to get the unvarnished truth when important trials such as this are done at a number of premier expert centers.

This is how the comparison stacks up, as of now:

FCR  vs PCR

Protocol Feature	FCR	PCR
Site	M. D. Anderson	Mayo / Ohio State
Number of Patients	224	65
Patient Characteristics
Median Age	58 years	62 Years
Rai Stage III & IV	33%	52%
High Risk FISH	NA*	45%
Unmutated IgVH	NA	58%
Positive CD38	NA	33%
Positive ZAP-70	NA	33%
Outcome
Overall Response	95%	96%
CR	70%	42%
nPR	10%	27%
PR	15%	27%
Response Duration	69% @ 4 years	50% @ 32 months
Toxicity
Deaths	2%	3%
Serious Infection	3% of courses	9% of patients
Neutropenia	52% of courses	58% of patients
Thrombocytopenia	5% of courses	21% of patients

* NA: not available.

While this is a useful comparison and we thank the Mayo researchers for making it available to the participants of their seminar, it is also a deeply frustrating comparison to me. Frustrating because it is so not apples to apples! It is more of an apples to kumquats comparison. Let me count the ways in which the two trials are non-equivalent. For starters, the patients selected for the two trials are not very comparable. The Anderson crowd had younger patients, and fewer of them were in the late Rai stages 3-4. Even more important from my perspective, we have none of the modern prognostic indicators on these patients treated at Anderson. Rai staging is hardly the last word anymore in describing patient cohorts! (Dawn of a New Era). For example, we have no clue how many of these patients were IgVH unmutated, or had the dreaded 11q and/or 17p deletions, something that a FISH test would have determined. The Leukemia Department of M. D. Anderson has one of the premier pathology labs in the whole country and I am surprised patients in this important trial were not better characterized. Or, if the tests had been done, it is hard to understand why the researchers have not published this important baseline information along with the rest of the results. The results obtained must be judged in the context of the patient cohort used for the study, and most experts today would agree prognostic indicators are a large part of that evaluation.

Moving on to the outcome comparison, the overall responses obtained by the two approaches are about the same. But the FCR group got a significantly higher percent of CR responses. The last item under the outcome section is more important, in my opinion. As we have seen in our recent review of the RF therapy (RF Risks and Benefits), getting a wonderful-sounding CR is of cold comfort to a patient unless it translates into a long lasting and trouble free remission and, in the final analysis, to longer overall survival. On that score, it is interesting that FCR appeared to fare better: 69% of them were still in remission 4 years later, whereas only 50% of the PCR patients were in remission after 32 months. For what it is worth, based on this less than rock-solid comparison, the FCR therapy seems to have more oomph to it, compared to PCR. I would feel a lot more secure in that last statement if I had a better fix on the comparability of the two patient groups, if it was a true apples to apples comparison.

Now let us look at the cost side of the equation. I hope by now you folks are all savvy enough to do that, before you sign on the dotted line for any clinical trial. Both FCR and PCR had comparable (low) percentages of patient deaths. The comparison becomes a lot harder when it comes to infections, neutropenia and thrombocytopenia. M. D. Anderson reports their statistics as a percentage of courses administered. Mayo/Ohio State report the same data as a percentage of patients treated. Even if we assume that most patients in the FCR trial finished an average of only 4 courses of therapy (remember, the FCR trial called for 6 courses — I am discounting this down to an average of 4, to take into account patients who may not have been able to handle all 6 courses and therefore got fewer than 6 courses), then the percent of serious infections for FCR goes from 3% of courses to 3 X 4 = 12% of patients, unless, of course, the same patient was counted as getting serious infections on more than one course. On this basis it would appear just about every patient in the FCR regimen suffered neutropenia, and a good 20% of patients had thrombocytopenia. On all three counts, it appears PCR had fewer problems.

Is this a completely kosher comparison? Can we be sure that multiplying by the number of courses accurately converts the Anderson way of stating the statistics to the Mayo / Ohio State way of doing it? Hardly. But it is the best we have right now. I wish the comparison was a lot more straightforward, the patients in the two regimens were more comparable, the same yardsticks were used in measuring toxicity and we did not have to do any funky conversions in order to compare the two sets of data. With all those caveats, this interim comparison seems to suggest PCR is less toxic, but possibly the lower toxicity is purchased at the expense of shorter remissions. Neither trial has been running long enough to comment on "Overall Survival", the one statistic that really matters to patients. Bottom line, as we have said many times before, in our opinion there is no free lunch here folks.

Finally, an Apples to Apples Comparison of FCR versus PCR !?

You will be pleased to learn of a phase III, double arm, randomized uncontrolled trial that was launched to recruit 280 patients in "A Prospective, Randomized, Open Label, Phase III Trial of Fludarabine, Cyclophosphamide, and Rituximab vs. Pentostatin, Cyclophosphamide, and Rituximab in Previously Untreated or Treated b-Cell Chronic Lymphocytic Leukemia". This trial is sponsored by SuperGen, the owner of the rights to pentostatin (Nipent is the brand name) and U. S. Oncology Research, which provides physicians' services related to cancer research. (The rights to Nipent have since been sold to Mayne Pharma — which itself will be acquired by Hospira, a spinoff of Abbott Labs — and it is hard to predict what that means. However, you can still read the Nipent product pamphlet.) The study promises to study both "good effects and bad" of the two combinations, but does not go into any details and therefore I have no clue exactly what that means. The trial seems to have been recruiting since December 2024, and is still recruiting as we speak. It has been very low key and I have to admit it went below my radar since this is the first time I have come across it. This is not surprising since the trial appears not to have been listed with www.clinicaltrials.gov until November 9, 2024. You can read the details of the inclusion criteria, etc., by clicking on the following clinicaltrials.gov link: NCT00254163.

While this large-cohort, phase III, double arm trial is obviously one we will be watching with great interest, I am a little cautious about the credibility of the study. My caution derives from the fact that it is a company-controlled trial, supervised by company personnel, and moreover the work is being done only at multiple local physicians' offices in the US. No major hospital and none of the CLL Research Consortium sites are participating in it. But let us not pre-judge it — we will wait until we see the formal publication of the results and go from there. We are assuming, of course, that there will be prompt publication of the results of the trial and full disclosure of relevant detail, something for which the pharmaceutical industry does not have the best reputation.

A Randomized Controlled Trial for FCR

Finally, the German CLL Study Group under Dr. Michael Hallek at the University of Cologne is doing a Phase III randomized controlled trial recruiting 600 patients to compare early stage but high risk patients treated early with FCR against a control group of similar high risk patients under observation only. Many hospitals in Germany and one in Austria are participating. The idea is to see if FCR therapy helps or hinders the process of improving length and quality of life for this particular patient cohort. German clinical trials have a reputation for solid trial design and attention to detail. The public listing of the trial is Jan 10, 2024, so this one is hot off the presses. You can read the details by clicking on the following clinicaltrials.gov link NCT00275054. If any of you are participating in the German trial or the SuperGen trial, do write and let us know how you are doing. I would especially like to see the detailed protocols and the patient information packets.

FCR + Mitoxantrone: Some Good News

If you are a frequent visitor to the CLL Topics website, you are no doubt familiar with our comments on this particular combination. You think FCR is a potent combination? Then you will love the next one in line, with the addition of mitoxantrone to the FCR regimen. While I am not a big fan of the concept that more is always better when it comes to chemotherapy, that was not my major beef with this clinical trial when it was first announced at M. D. Anderson. We were deeply concerned that their clinical trial protocol did not meet the required standards for patient safety.

Like its more famous cousin doxorubicin, mitoxantrone has very clearly identified risks of cardiac toxicity. There is a recent "Dear Doctor" letter from the FDA identifying this risk, and requiring that patients be pre-screened for cardiac sufficiency before they are given mitoxantrone. We were deeply concerned that chemo-naïve patients were being recruited for this trial with no requirement in the protocol to warn them of or screen them for this important risk factor. Not only were these early patients not screened for cardiac function prior to recruitment, there was no mention of potential toxicity in the trial description on the M. D. Anderson website, nor any mention of it in the patient information packets that we saw. This was a serious omission from our perspective, one that potentially endangered patients that signed up for this trial. We contacted the Principal Investigator for the trial — and you can read our letter as well as his response (Mitoxantrone Plus FCR; More on Mitoxantrone plus FCR). We also published a thoughtful and detailed analysis of the issues by our own Dr. Terry Hamblin (More on Mitoxantrone plus FCR).

Additionally, we contacted OSI Pharmaceuticals, the manufacturer of mitoxantrone and co-sponsor (with M. D. Anderson Cancer Center) of the trial. We pointed out to the company that the FCR + Mitoxantrone clinical trial protocol did not meet the guidelines for safety as set forth by the FDA, since there was no effort to screen and exclude patients on the basis of cardiac function as measured by LVEF (left ventricle ejection fraction). We did not agree that this was a question open to debate, handled by the researchers at their discretion and as they saw fit, but a mandated guideline that had to be met. We also published a description of the design of the European version of this combination (Mitoxantrone plus FCR - Brit. Version), where, in sharp contrast to the M. D. Anderson design, cardiac function was very much a part of the inclusion criteria, established by means of appropriate heart scans.

Last but not least, we voiced our frequent complaint that the trial was not listed on www.clinicaltrials.gov or other public trials registry. This is now the standard of all-well conducted clinical trials. It is no longer acceptable that clinical trials are announced solely on company or institutional websites. Public announcements and public scrutiny of clinical trials is at the heart of enforcing standards and patient safety, we will keep bringing up this point with researchers until there is broad compliance.

Well, I guess if you keep tilting with windmills, even very large and powerful windmills, once in a while you actually win!

Below is the link to a listing of the FCR + M clinical trial, newly published on www.clinicaltrials.gov . Our articles and letters on the subject were dated in early part of August, 2024. On Nov 14, 2024, a listing for this clinical trial was received by the NIH and subsequently posted on www.clinicaltrials.gov. Even more important, please notice exclusion criterion # 6 reads "Symptomatic heart disease (NYHA class>=3) or LV ejection fraction <40% (by MUGA or echocardiogram)" as grounds for excluding patients from the trial!! I am tickled pink to see this important change, my congratulations to the investigators and the sponsoring company for taking our suggestion to heart and doing the right thing, making this addition to their exclusion criteria.

http://www.clinicaltrials.gov/ct/show/NCT00254410?order=4

Now we sit back and wait to see how this very potent drug combination plays out in our patients. My sincere request to the researchers, please publish your results promptly in detailed, full length articles in peer-reviewed journals. These are life and death therapy decisions that patients must make, and detailed information from clinical trials such as this is at the very core of making smart decisions. Transparency and prompt reporting are a necessary counterbalance to the willing risks and sacrifices made by patients volunteering to enlist in clinical trials.