• An Update -- 1/4/01

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At the recent Mesothelioma Conference in Chicago, Dr. James Rusthoven presented data regarding the efficacy of various clinical trials using ALIMTA^(R) (pemetrexed disodium), which is a new chemotherapy drug made by Eli Lilly. Alimta is a novel antifolate which inhibits several enzymes that are involved in the division of cancer cells. The chemo is a systemic drug that is injected into the blood stream.

Initial phase II trials had focused on tumors of the colon, lung, breast and mesothelioma. Dr. Rusthoven reported that Lilly had recently completed accrual of its Phase III trials (450 patients, world wide).

The following summarizes my notes from the conference. I have tried to attribute the opinions to their source.

Phase I Trial: Alimta + Cisplatin

• Total Patients enrolled: 54
  
• Colorectal cancer, mesothelioma, colorectal, melanoma, NSCLC
  
• 11 patients had malignant mesothelioma.
  
• 6 of the 11 mesothelioma patients showed a confirmed response

Note: A "response" is a reduction or shrinkage of tumor dimensions as measured by CT scan. There is always the question of whether by CT tumor can be differentiated from fluid.

Note: Dr. Hansuciske (sp?), who presented the slides, stated that of the 11, 5 had a "partial" response, which differs from the slides. But he did say the response was "dramatic."

• For the mesothelioma patients, the Alimta + Cisplatin regimen produced a 48% response rate. Most standard chemotherapy regimens produce response rates of between 7% and 20%.

Phase I Trial: Alimta + Carboplatin

• 29 malignant mesothelioma patients enrolled
  
• 9 of 29 have positively responded
  
• Response rate: 31%
  
• 19 of 27 showed clinical improvement (70%)
  -note: I don't have definition of "clinical improvement," but I gather it means that the patient's symptoms (shortness of breath, pain, etc) were relieved somewhat.

Phase II Single Agent Alimta Trial

• 62 malignant mesothelioma patients enrolled
  
• Age: 62 (range 40-80)
  
• M/F ratio: 5.2/1
  
• Overall response rate: 14.5% (9 of 62)
  
• Patients partially supplemented with vitamins (folate) had 60% response rate (3 of 5); non vitamin supplemented: (5%, 1 of 17); fully vitamin supplemented, 18% (5 of 40). Vitamins included folic acid and B/12.
  
• The addition of low dose folic acid and B/12 "has markedly improved the toxicity previously seen with Alimta therapy."
  
• Median duration of response: +10.8 mos
  Median time to progression: 5.4 mos
  Median survival: 10.7 mos

Phase III Trial (ongoing, 450 accrued patients, worldwide)

• Objectives are to compare survival times, compare tumor response rates, compare clinical benefit (pain, intensity, shortness of breath, pain control), compare pulmonary function tests, compare lung density, compare toxicities, etc.
  
• Alimta + Cisplatin vs. Cisplatin only
  
• Interim analysis expected in June or July 2001

At the outset of the conference, Dr. Nicholas Vogelzang reported on the standard chemotherapy agents and their respective response rates:

1. Doxorubicin: 7.3% (10 mos median survival)

2. Doxorubicin + cisplatin: 14% (8.8 median survival)

3. Mitomycin/cis:26% (7.7 median survival)

4. Onconase: * 43%

5. Onconase vs Doxorubicin:

6. CPT 11: 0%

7. "The best drugs seem to be the most toxic." "The slash, burn and poison" approach has had little impact.

Dr. Karen Antman of Columbia Presbyterian in New York City discussed other novel agents that have been used for mesothelioma. Like most of the doctors, she began with the grim statistics and dire conclusion that "no good treatment for mesothelioma exists." She acknowledged that different hospitals take different approaches, largely because there is no standard of care. Dr. Antman also urged physicians nationwide to collaborate, to get together, and compare notes, in the hopes of sharing the good and bad news.

Regarding surgery, Dr. Antman reported that the median 5 years survival of mesothelioma patients who have undergone pleurectomy fared better than those who had the extra pleural pneumonectomy (EPP). She also said that the EPP would at best add only a few months beyond the survival of a patient who simply opted for the talc pleurodesis (which is far less painful and has far fewer complications than radical surgery).

In his presentation, Dr. Harvey Pass said with respect to prognosis and the dimensions of the tumor that "size does matter." Surgery plus follow up therapy, such as chemotherapy and or radiation, has been shown to increase the median survival of mesothelioma patients. But he noted that the tumor seems to find a way to come charging back (50% of the post-surgery patients experience recurrence within 8 months). Regarding the surgical option, Dr. Pass cited the research by Dr. Valerie Rusch at Sloan Kettering that the median survival for pleurectomy vs. EPP patients is about the same. The size of the tumor had some relationship to the risk of nodal disease, and spread to the lymp nodes indicated a poorer prognosis.

Regarding chemotherapy, Dr. Antman reported that a team of doctors in Germany published a response rate of 38% for 69 mesothelioma patients who received methrotrexate. (Note: Dr. Eric Vallieres at the University of Washington also uses methrotrexate, along with Velban and cisplatin, and he has reported a response rate of 48-50%). Methrotrexate is in the same class of drugs as Alimta. As I understood it, she raised the issue that the amount of drug administered in the German trial was much higher than the levels administered in the U.S.

She said doxorubicin was the "gold standard" for mesothelioma and its response rate is only 18%. A trial using gemcitabine as a single agent yielded a response rate of only 7%. However, in combination with other drugs, like cisplatin, the response rates shoots up to 48% (referencing a phase II trial of 21 mesothelioma patients). Dr. Antman questioned the reliability of the 48% response rate for Cisplatin + Gemzar (cisplatin), as she opined that the number was likely lower.

Regarding hyperthermic perfusion (heated chemotherapy application during surgery), Dr. Antman expressed hope that it would be promising, but chagrined that there was no published data showing its efficacy. Dr. David Sugarbaker, who has used the technique, has not published any data and was not present at the conference. Finally, Dr. Antman urged that the skill of the surgeon performing the operation was "a big factor" in the survival of the patient and she noted that there were very few surgeons nationwide with the expertise to tackle this tumor.

Dr. Hedy Kindler of the University of Chicago discussed angiogenesis inhibitors for the treatment of mesothelioma. She has been investigating a clinical trial using an angiogenesis inhibitor drug called SU-5416. The enrollment is 19 patients, from June 2000 to April, 2001. She found "preliminary evidence of tumor regression in 4 patients." She noted that the drug was "well tolerated" but not without the risks of complications like thrombosis, for which the patients receive cumadin.

As Dr. Vogelzang said so well, summarizing where we are and how far we've come in terms of mesothelioma therapies, "We've hit a bunt single. We've taken a small step forward." To expand on our base of knowledge and increase our chances of finding meaningful therapies, Dr. Vogelzang stressed we need more patients to enroll in clinical trials, we need more financial resources to undertake these trials, and we need drugs or biological agents that target the mesothelioma tumors directly.

Roger G. Worthington

What's New in Mesothelioma?, 37th Annual Meeting of ASCO, May 15, 2001

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* Footnote

There has been considerable confusion over the response rate for Onconase. The response rate is not generally reported in Alfacell's abstracts and presentations. It is not reported on their website. This is the number that Dr. Vogelzang mentioned. I looked for some abstracts for both the phase II and the phase III trials. In the Phase II, the response rate was indeed 11% (63 patients, four patients achieved partial responses; 3 additional patients achieved minor responses.) Another 25% had stabilization of previously progressive disease for 3 to 8 (plus) months duration.

The abstract for the Phase III does not provide response rates at all, though it specifically says they were measured. It does say the one year survival in the TTG subsets (made by throwing out the worst prognosis patients), was 46.2%, so maybe this is the source of Dr. Vogelzang's number.

The conclusion of the Phase III abstract reads "Onconase is active in UMM, and may be superior to Doxorubicin in certain subsets of (mesothelioma) patients." Doxorubicin's response rate is at 7.3%. I spoke to one doctor at the University of Chicago who confirmed the response rate was around 11% for Onconase.

In the Phase III trial, the median survival time (MST) was 7.7 mos. In the target treatment groups, defined by excluding the worst prognosis patients, MST was 11.3.

*** POSTED ON APRIL 26, 2001 ***

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The information contained in the above footnote is taken from an interim analysis on March 1, 1997, of the first 63 patients in the study. The interim results are contained in an article entitled "The Use of Onconase for Patients with Advanced Malignant Mesothelioma," available at http://www.mesothel.com/pages/onconase.htm.

The final results of the completed Phase II trial were published in the January 1, 2002, issue of the Journal of Clinical Oncology, available at http://www.mesothel.com/pages/onconas9.htm. A phase III trial is currently ongoing, for which more information may be found at http://cancernet.nci.nih.gov.