SEATTLE ( TheStreet) -- Can Cell Therapeutics ( CTIC) and its lymphoma drug pixantrone withstand the withering scrutiny of U.S. drug regulators?

The answer comes Feb. 10, when Cell Therapeutics travels to suburban Washington D.C. to make its case for pixantrone's approval to a panel of cancer experts convened by the U.S Food and Drug Administration.

The FDA's advisory panel will be reviewing data from a phase III study of pixantrone in patients with advanced, aggressive non-Hodgkin's lymphoma. The "EXTEND" study was conducted under a Special Protocol Assessment from the FDA, and the results, as presented by Cell Therapeutics to date, appear to be positive.

Of course, clinical data from "positive" phase III trials always looks great when pitched by the company developing the drug. The truth about a drug's efficacy is often something different and far less robust, especially after FDA reviewers finish picking apart the data line by line.

If the pixantrone data closet does have skeletons -- and let's face it, no drug skates through an FDA review unscathed -- here's where they might be found:

1. Missing patients?

Cell Therapeutics designed the pixantrone EXTEND study in 2003 - 2004 with the intention of enrolling 320 patients. In March 2008, however, Cell Therapeutics announced that it halted enrollment at 140 patients.

Will FDA accept the results from this study, given that only 40% of the planned patients actually enrolled? How does the drastically smaller number of patients effect the statistical powering of the study? And given the fact that the study is open label -- meaning doctors and patients know who's getting pixantrone and who's getting a comparator drug -- what amended rules were put in place to say that 140 patients were sufficient to prove pixantrone's efficacy?

2. Does Cell Therapeutics really have a Special Protocol Assessment?

A Special Protocol Assessment (SPA) is essentially a formal agreement reached between a drug company and the FDA that says the design and endpoints of a phase III clinical trial are sufficient for a drug's approval.

Cell Therapeutics executives, including CEO Jim Bianco, have stated repeatedly in public that the EXTEND study of pixantrone was conducted under an SPA from the FDA. Many of the company's recent press releases, including one from April 14, 2009, also make the claim.

But the SPA claim is missing from Cell Therapeutics' filings with the Securities and Exchange Commission. The EXTEND trial is discussed in every one of the company's 10-K reports since 2003, but never does the company state that the study has an SPA.

Cell Therapeutics issued a press release on March 4, 2004 to announce the start of the EXTEND study. The SPA is mentioned but in an indirect way:

"Cell Therapeutics, Inc. announced that the U.S. Food and Drug Administration has provided guidance through the Special Protocol Assessment (SPA) process for a randomized sic pivotal trial of Pixantrone in the treatment of relapsed, aggressive non-Hodgkin's lymphoma (NHL)," the press release states. Emphasis added.

"Provided guidance?" What does that mean, exactly?

This may seem like a minor point in the grand scheme of things, but it could also be vitally important, especially if FDA has a problem with the smaller-than-designed enrollment in the EXTEND trial. If the EXTEND trial was not conducted under an SPA and FDA finds data from 140 patients insufficient, the agency could ask the company to conduct an entirely new study as a condition for pixantrone's approval.

3. How reliable are the response rates in the EXTEND study?

Before I get to this issue, let's review the details and data (per Cell Therapeutics) that came out of the EXTEND study:

The PIX 301 "EXTEND" trial (download the posters here) enrolled 140 patients with relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL). The patients, all of whom had received two or more prior therapies, were randomized to receive either pixantrone monotherapy or a doctor's choice of other single-agent chemotherapies.

Cell Therapeutics says the EXTEND study met its primary endpoint, with 25.7% of pixantrone patients achieving a complete response (CR) or an unconfirmed complete response (CRu) compared to 7.1% of patients in the control arm achieving a CR/CRu. The result was statistically significant.

With that as background, watch for how the FDA adjudicates the patients deemed to be unconfirmed complete responders (CRu) because in recent years, at least one influential academic group of lymphoma researchers no longer uses CRu as a valid measurement of disease response. Patients are now characterized as complete responders (CR) or partial responders (PR.)

Six patients treated with pixantrone were deemed unconfirmed complete responders, according to Cell Therapeutics. If some or all of these patients are actually found to be partial responders by the FDA, the 25.7% CR/CRu response rate in the study could fall dramatically. If that happens, the EXTEND study may no longer meet its primary endpoint with statistical significance.

The secondary efficacy endpoints of the EXTEND study were also met, according to Cell Therapeutics. Median progression-free survival for pixantrone patients was 5.6 months compared to median PFS of 2.6 months for patients in the comparator arm -- statistically significant.

A positive trend in median overall survival was also observed favoring pixantrone (10.2 months) over the comparator treatments (6.9 months.)

Would these additional efficacy data sway the FDA to approve pixantrone even if the primary endpoint of the EXTEND study -- the response rate measured by CR/CRus -- was not met? Not likely, for when a study misses its primary endpoint, all secondary endpoints, including survival, become exploratory in nature, only.

4. Were the patients in the comparator arm of the study treated with the best drugs available?

The 7.1% CR/CRu rate amongst patients treated with one of six different single-agent chemotherapy drugs in the comparator arm of the study seems low, especially compared to the response rates found in other similar trials. (The FDA compiled a chart of single-agent drug trials in aggressive NHL patients as part of its unflattering 2004 review of Marqibo, another lymphoma drug. You can find it here.)

If the FDA finds that patients were treated with substandard drugs in the comparator arm of the study, or if the FDA believes that more efficacious drugs should have been used, it could, like the point above, raise questions about the benefit of treating patients with pixantrone.

5. How sick really were the NHL patients in the EXTEND study?

One of the central arguments that Cell Therapeutics makes in support of pixantrone's approval is that the NHL patients in the EXTEND study benefitted from the drug despite the advanced stage of their disease. These patients, to put it simply, were the sickest of the sick and were no longer responding to other available treatments. Yet, they responded well to pixantrone.

But is that really true? The median age of pixantrone patients enrolled in the study was 60, in the comparator arm it was 58. Patients with aggressive NHL under the age of 65 often undergo stem-cell transplants as part of the normal course of therapy. If the EXTEND patients were, in fact, the sickest of the sick, you'd expect the rate of stem-cell transplantation to be relatively high.

It isn't. Sixteen percent and 14% of the pixantrone and comparator arm patients, respectively, underwent prior stem-cell transplants, according to the EXTEND study data made available by Cell Therapeutics.

6. Where in the world did pixantrone actually work?

The EXTEND study was an international study but most of the patients were enrolled outside the U.S. Geographic disparity of response to pixantrone could become a troublesome regulatory issue, if for instance, U.S. patients are completely missing from those who recorded complete responses or unconfirmed complete responses.

7. Is pixantrone less cardio-toxic?

Pixantrone belongs to the anthracycline class of chemotherapy drugs, which are well known to cause heart failure at high doses and/or prolonged exposure. Pixantrone is designed to be less toxic to the heart, allowing it to be used in patients that have been treated previously with other anthracyclines, according to Cell Therapeutics.

This claim will likely be a review issue on Feb. 10, with the FDA and the panel experts going over pixantrone's safety data closely. Almost 9% of pixantrone patients experienced a serious cardiac event in the EXTEND study compared to 4.5% for patients in the comparator arm, according to the data presented to date by Cell Therapeutics.

If FDA and panel experts reach the conclusion that pixantrone is not more heart safe than other anthracyclines, Cell Therapeutics loses one of the most important data points it needs to market the drug effectively (if approved).

The last FDA advisory panel for blood cancer drugs in September was very rough, with Genzyme ( GENZ) and Vion Pharmaceuticals both receiving negative votes. Allos Therapeutics ( ALTH) emerged victorious, but even there, the debate and review were no holds barred. Cell Therapeutics best be prepared for a brawl if it's going to walk away with a vote for approval.

-- Reported by Adam Feuerstein in Boston.

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Adam Feuerstein writes regularly for TheStreet.com. In keeping with TSC's editorial policy, he doesn't own or short individual stocks, although he owns stock in TheStreet.com. He also doesn't invest in hedge funds or other private investment partnerships. Feuerstein appreciates your feedback; click here to send him an email.

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