Unscrubbed Aldoxorubicin Phase 3 Pivotal Trial Data Approaches Maturity: The Dirty Truth

| About: CytRx Corporation (CYTR)
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Summary

Primary endpoints data: Three PFS cohorts required by FDA.

Secondary endpoints and safety data: The four measures.

Supporting Phase 2 studies and FDA breakthrough statuses.

FDA landscape for STS drug approval favors options for MDs.

Aldoxorubicin's imminent chance of approval at 99%.

CytRx Corporation (NASDAQ:CYTR) has released unscrubbed data of its Phase 3 pivotal trial for aldoxorubicin as a monotherapy in soft tissue sarcoma. As this successful clinical trial nears completion, it has taken many people by surprise because interim data was perceived by only scholars as a success. However, as previously described by several authors (see here and here), it is no surprise at all that the trial has met several, if not all, primary PFS endpoints and will pass FDA's rigorous approval requirements very soon upon full maturation.

Because there was quite a bit of data included in the press release, and some data seemingly omitted, we will attempt to explain points of active contention. This article is objectively pro-CYTR, with only 30 years of scientific scrutiny as our guide, but balanced articles exist, such as here and (con) here. I want to admit that I really enjoy the articles that adversaries submit. If we all agreed on all points in life, there would be fewer frontiers of discovery broken in science. This philosophically makes the tremendous breakthrough against tumor barriers spearheaded by aldoxorubicin much more pleasing to observe.

As the company stated in the press release, the primary endpoints are three cohorts of PFS. CYTR didn't state what the significant increase in PFS for the aldoxorubicin patients was as a unit of time in the three cohorts, but simply reported statistical significance respectively. The company also did not state at what time point the data that they provided was. They merely displayed raw data hazard ratio and p values to qualify the future FDA submissions. Some people might not understand why it is not presented in its entirety and see it as a "dodge" or "doctored data", such as this article states. There is a very good reason. The company is obligated to present specific data at an upcoming cancer conference, and these presentations legally define a responsibility NOT to present "previously reported" data. In fact, if companies do not adhere to this, there are very meticulous whistle blowers, geniuses for detail and as sincere as they are brilliant, who will lead no less than 30 law firms per week against a company for doing that, such as was the case this summer with Immunomedics (NASDAQ:IMMU) which you can read about here. I don't know about you, but I don't want to mess with any attorneys, nor am I taking that bait!

FDA will require CYTR to present three PFS cohorts for the primary endpoint analyses in the future NDA, which is to include all secondary endpoints including OS and safety as well. These were liposarcoma plus leiomyosarcoma (the two most common types of STS), North America plus Australia cohort, and the total population. You read that right. These categories were not "data mined" according to some agenda to find something good about the study (and even if it had, the massive patient numbers in these categories are a resonant symphony of harmonious crescendo). For ease in referring to the statistically significant data approaching maturity, the table posted in the press release is shown below.

PFS, DCR and ORR data are summarized in the following table:

Phase 3 Aldoxorubicin Efficacy Results

N

Aldoxorubicin

Investigator's Choice

P Value

All patients with Leiomyosarcoma and Liposarcoma (PFS)

246

HR = 0.62 (95% CI 0.44-0.88)

0.007

North American1 patients

312

HR = 0.71 (95% CI 0.53-0.97)

0.028

Disease Control Rate (DCR)2

32.9%

19.2%

0.007

Objective Response Rate (ORR)

8.7%

3.3%

0.058

All patients

433

HR = 0.81 (95% CI 0.64-1.06)

0.120

Disease Control Rate (DCR)2

29.4%

20.5%

0.030

Briefly, CYTR already met primary endpoints for the most two common types of STS, 246 patients, in terms of statistical significance. It also met the primary endpoint for PFS in the North America plus Australia cohort in all types of STS, a whopping 312 patients. It's very interesting that the data reached statistical significance against the physician's choice in areas of the world where the standard of care is best, before it will meet statistical significance in the rest of the locations upon maturity, and that's a lesson to us all. The comparator arm treatment of choice was likely to be the best for those patients in the technologically advanced locations. For more about hospital choice and standard of care, read here. It should encourage all of us that we make a difference when we support our doctors and patients with cancer. The better the quality of care, the sooner the successes of treatment populations.

The third primary PFS endpoint, total population PFS, demonstrated a p value approaching statistical significance as we near completion. Critics have published that means this study failed in its third primary endpoint finding. But as already explained, it's simply still maturing. So basically what this means is when you add in the clinical sites around the globe that are outside of FDA's jurisdiction, the reproducibility of aldoxorubicin's benefit is slightly lower in 120 (433 total patients minus 312 North American and Australian patient total) minus remaining patient population that did not have liposarcoma or leiomyosarcoma (which was 246), which is estimated to be about 50 patients with some other disease subtype from some other place, extending the time required for patients in the North American and Australian data cohort to enable total population maturity. A lot of the literature refers to effects of this common global phenomenon as a difference in standard of care, such as reported here and here. It's also likely that misdiagnosis occurs in lower standard of care regions as well, meaning that some of these patients were more likely to have other confounding variables. Arguments that the third primary endpoint is a reason that this study has failed are preposterous, especially when we look at the landscape of STS approvals this year by FDA. But first, we look at the supporting data (secondary endpoints and other studies with aldoxorubicin). Even the most meticulously groomed skeptic, polished to the scalp, would admit that FDA approves drugs based solely upon secondary endpoints.

Secondary endpoints for the study include overall survival (OS), observed response rate (ORR), and disease control rate (DCR). Rather than restate the data here, of note were that DCR was reported as ORR plus stable disease for four months, and all were statistically significant for meaningful benefit of aldoxorubicin. Because ORR and DCR do not require as much follow-up time, it's likely that these data will not mature any further. ORR approached statistical significance when reported as an independent statistical measure, in the raw analysis, for North American and Australian cohort. So in this case, the foreign geographical cohort performed very slightly better for this measure, a slight inverse of PFS. OS is expected in 2017, but obviously, since the patients are dosed until progression, the favorable ORR, DCR, and PFS numbers indicate it's not likely for OS to miss significant benefit upon its longer maturation curve. This is a very important point because most other drugs for STS have a low correlation between PFS and OS as reported here. Aldoxorubicin is clearly a game changer in several aspects, as one would expect given its unique mechanism of tumor capsule penetration.

Safety continues to be a strong point for aldoxorubicin. Some potentially serious but manageable side effects were found with aldoxorubicin, but low grade. Aldoxorubicin, which delivers 3 to 4 times the dose of doxorubicin to patients than doxorubicin in its free form administration, does not cause cumulative cardiotoxicity in contrast to doxorubicin. Because aldoxorubicin specifically delivers doxorubicin to the tumor itself and very little to healthy tissues, it has demonstrated superior safety in clinical studies of over 600 patients over seven years. Other treatments of choice can lead to more serious liver and kidney issues etc., reported here. Aldoxorubicin is clearly demonstrating itself as a superior option for physicians having tumor patients with existing safety complications precluding use of alternatives.

Another study supporting aldoxorubicin approval for STS reported here is equally impressive, but with even greater potential impacts for patients. This Phase 2 study using aldoxorubicin as a combination therapy with ifosfamide and mesna rocketed out a whopping 97% disease control rate was reported at four months into the study. The current standard of treatment is only 15-30% disease control at the four-month time frame. At first, I didn't make too much of this result until it persisted at the six-month update. Perhaps this is what led Dr. Sant Chawla, director of the study, to state possible FDA breakthrough therapy status for aldoxorubicin in the most recent company conference call, which you can listen to on the company website here. Several of the aldoxorubicin-treated patients became eligible for a curative surgical procedure, having greater than 50% reduction in tumor size. The number of partial response level patients eligible for curative measures increased as the study reported updates. In addition, a patient who was only stable disease in the first update improved to partial responder with greater than 20% reduction in tumor size, indicating dosage until progression is rescuing patients in a wide spectrum of disease control. It should also be noted that when surgically excised tissues were biopsied they showed no signs of active tumor activity in the investigation reported here. Aldoxorubicin was also shown to be present in the lesions.

Although beyond the scope of this article, the preliminary results of the Phase 2 SCLC study, of which there is no current FDA approved label for treatment, are very encouraging as the PFS is not yet reached. What this means is that the study is working, and that's a 2.5 billion dollar per year market, virtually untapped. Scientists have noted that lung tumors run a little more acidic than most tumors, so this comes as little surprise but as a pleasant finding. This is the second indication aldoxorubicin is likely to obtain FDA-granting breakthrough-therapy status. SCLC approval will take some time as it will require its own Phase 3 study and NDA submission, but off-label or SPA with marketing approval are certainly possible given there is no current treatment for this devastating cancer. Still, with a probable annual market of approximately 4 billion dollars per year, aldoxorubicin is poised to help a lot of patients in the battle for survival.

FDA landscape for STS drug approval in general is regarded as relaxed. Trabectedin was approved by FDA only this year in spite of missing primary endpoints in Phase 3, and has a limited efficacy, as reported here. FDA is strongly favoring giving physicians more options for treatments, especially in cancer. Trabectedin increased PFS by about 2 to 2.5 months, with aldoxorubicin more likely being in the 5 to 7-month range for monotherapy, and it may be quite a while before we know for the combination therapy, with 97% DCR at six months. Hopefully, it takes a long time to find out! All that and we're still not even done stating the case for aldoxorubicin's chances of FDA approval.

The Phase 3 study reports 95% inclusion in the press release. And nowhere does it say this is 95% complete, it just merely stated that the study met statistical significance at that time. I do not regard this as a statement that the study is complete. PFS is likely ongoing, resulting in higher and higher efficacy measures via maturation and super-responder weighting with each evaluation. In my experience at the director of clinical research level, you want that data published as soon as possible for your client, so some of the super-responders in the study are probably not even disease progressed at the time that data set met statistical significance either. When this last 5% progresses, they can be uncensored, and that will bring the statistical significance up if the data is not already locked. It's my experience that 95% inclusion means the top 2.5% responders and the bottom 2.5% non-responders will be thrown out as statistical outliers. That will push the statistical significance up as we narrow the focus of the bell curve for drug response. Data scrubbing is yet to occur as well. Every drug study that has ever been passed to FDA has been examined using fair standards for looking at data. As long as the procedures done are reported, FDA can decide according to common standards if it will accept the data. Such techniques include exclusion of the worst and best 1, 2, 3, 4, or 5 clinical sites as a way to throw out statistical outliers, for example, as long as the data is paired or balanced. It's also possible to have other outliers thrown out for a variety of reasons including age, misdiagnosis, stage of inclusion, and presence of other diseases otherwise undetected, etc. The cartoon below explains exactly how these distributions tighten with statistical manipulations all permitted by FDA.

stats cartoon

We here at Strong Bio admit this ghost is hardly scary to most of our readers, but the reality of this study being close to maturation and nearing final conventional data processing ought to scare the hell out of anyone shorting the stock. I admit I'm long on the stock, but I don't want anyone financially hurt in the process of cancer treatment progress.

Disclosure: I am/we are long CYTR, IMMU.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: I'm trying to select CYTR as primary ticker but it won't let me.

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