MESOTHELIOMA :TREATMENT, RESEARCH & CLINICAL TRIALS

Methotrexate "cousin" effective against pleural mesothelioma

Reuters Health
Posting Date: May 21, 2002

Last Updated: 2002-05-21 14:03:54 -0400 (Reuters Health)

ORLANDO, Florida (Reuters Health) – Pemetrexed, a drug related to methotrexate, is the first agent shown to be effective against malignant pleural mesothelioma, an aggressive neoplasm associated with asbestos exposure, researchers reported here on Monday.

Study author Dr. Nicholas Vogelzang, director of the University of Chicago Cancer Research Center noted that patients generally live about 6 to 9 months after diagnosis and the disease is marked by severe pain and dyspnea.

Pemetrexed (Alimta; Eli Lilly) was shown to add an average of 3 months to patients’ lives, Dr. Vogelzang told attendees of the American Society of Clinical Oncology’s annual meeting.

"We now have a treatment that not only treats this disease but also improves symptoms," he said. "This is the first time we’ve ever documented an improvement in mesothelioma survival."

Oncologists at the meeting were enthusiastic about the findings. "This is the first demonstration of a really effective drug for this disease," said ASCO president Dr. Larry Norton, of Memorial Sloan-Kettering Cancer Center in New York.

An estimated 2500 Americans are diagnosed with mesothelioma annually, Dr. Vogelzang said, but that number is expected to rise over the next 20 years.

The study of 448 patients found that those receiving pemetrexed plus cisplatin survived an average of 1 year, compared with 9 months for those on cisplatin alone. Results also showed that 41% of the tumors shrank in the study group versus 17% of the tumors treated with cisplatin alone. Patients receiving pemetrexed also reported less pain and a better overall quality of life, Dr. Vogelzang reported.

Pemetrexed treatment also caused serious adverse effects, such as neutropenia, severe diarrhea and stomatitis, and was linked to initially higher mortality. The researchers found that the drug caused elevated homocysteine levels and decreased levels of vitamin B12 and folic acid. However, vitamin supplements diminished the severity of adverse effects, Dr. Vogelzang said.The supplements also appeared to boost the effectiveness of the drug, he noted.


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Onconase plus Doxorubicin vs. Doxorubicin ( malignant mesothelioma )

see: http://cpmcnet.columbia.edu/dept/medicine/mesothelioma/clinmeso.html

Title: Multicenter randomized comparative phase III trial of onconase plus doxorubicin vs. doxorubicin in patients with malignant mesothelioma (part II)

Eligibility Requirements:
Histologically verified diagnosis of malignant mesothelioma
Pathology slides must be available for independent review
Patients aged 21 years or older
Chemotherapy naive or 1 prior chemo (excluding doxorubicin)

Treatment Plan:
Randomized to either Onconase plus doxorubicin or doxorubicin alone
Group I: Onconase will be given as a bolus intravenous infusion over 30 minutes weekly followed by a bolus intravenous infusion of doxorubicin every 3 weeks
Group II: Doxorubicin will be given as a bolus intravenous infusion every 3 weeks


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Trimodal Therapy- Peritoneal Mesothelioma

Title: Phase II trial of combined resection, intraperitoneal chemotherapy, and whole abdominal radiation in peritoneal mesothelioma

Eligibility Requirements:
Histologically confirmed malignant peritoneal mesothelioma
0-2 prior chemotherapy regimens allowed
At least 6 weeks since chemotherapy
No prior radiation to abdomen or lower chest

Treatment Plan:
Exploratory laparotomy will be done to try to remove all lesions > 1cm. Three to 4 weeks later, doxorubicin, alternating with cisplatin and gemcitabine, will be administered intraperitoneally for approximately 12 weeks. Gamma-interferon will be given weekly for the last 4 weeks of chemotherapy. After a second- look surgery, patients will commence radiotherapy, which will last 5-7 weeks


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Perioperative Gemcitabine and Cisplatin

Title: Phase II trial of perioperative gemcitabine and cisplatin chemotherapy in resected pleural mesothelioma


Eligibility Requirements:
Histologically confirmed malignant pleural mesothelioma
No prior chemotherapeutic regimens

Treatment Plan:
For patients referred prior to surgery: Chemotherapy will be given for 6 weeks followed by surgical removal of disease-affected lung tissue. This will be followed by another 6 weeks of chemotherapy, radiation therapy and another 6 weeks of chemotherapy.
For patients referred after surgery: Surgical removal of disease-affected lung tissue will be followed by 9 weeks of chemotherapy. This will be followed by radation therapy and another 9 weeks of chemotherapy.


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ALIMTA and Cisplatin

Title: Open-Label Study of ALIMTA (pemetrexed) in Combination with Cisplatin for Chemonaive Patients with Malignant Pleural Mesothelioma


Eligibility Requirements:
Histologically confirmed malignant pleural mesothelioma
No prior chemotherapeutic regimens
Prior radiation more than 2 weeks

Treatment Plan:
ALIMTA will be given as a 10-minute intravenous infusion on day 1 of a 21-day cycle. Cisplatin will be given as a 2-hour intravenous infusion on day 1 of a 21-day cycle.


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Chemotherapy combination promising for mesothelioma

Reuters Health
Posting Date: August 13, 2002


Last Updated: 2002-08-13 12:52:47 -0400 (Reuters Health)

LONDON (Reuters Health) – A new chemotherapy combination has shown "remarkable" activity against mesothelioma in an early study, British researchers reported on Tuesday.

Malignant pleural mesothelioma is increasing in incidence in most countries and has shown a poor response to systemic chemotherapy, the investigators write in their report, published in the Journal of Clinical Oncology for August 13. Approximately 250,000 people are expected to die from the disease in Western Europe over the next 35 years, they note.

But the combination of a new drug called pemetrexed, developed by Eli Lilly, with carboplatin could be an effective treatment for the hard-to-treat condition, Dr. Hilary Calvert from Newcastle General Hospital and colleagues say.

The researchers administered the two drugs to 27 patients with malignant pleural mesothelioma in a Phase I dose-escalating study.

"The drug combination showed remarkable activity in mesothelioma," Professor Calvert said in a news release. "Indeed, our study provided the first convincing demonstration that pemetrexed [and] carboplatin could be useful in the treatment of the disease."

Of 25 patients who completed the study, 8 showed a partial response, while 70% of patients noticed an improvement in symptoms, often after just 2 courses of chemotherapy.

The median survival time in the study was 451 days, or over 14 months. A handful of patients have survived for 3 years or more. Previously, people diagnosed with mesothelioma could expect to survive for 6 to 8 months, the University of Newcastle said.

The chemotherapy triggered neutropenia, leukopenia and thrombocytopenia, but these toxicities were usually short-lived and "caused few clinical problems," the researchers write.

A multinational, randomized trial has since shown an improvement of survival and symptoms, according to the news release.

"Mesothelioma is a serious condition that is difficult to treat, so this is an important development," Dr. Lesley Walker, director of cancer information at Cancer Research UK said in the news release. "We now need to look closely at the drug’s performance in the next stages of clinical trials to see how it compares to other anti-cancer drugs."

Journal of Clinical Oncology 2002;20.


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MESOTHELIOMA CLINICAL TRIAL INFORMATION

Summary: Phase II trial of combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for treatment of peritoneal mesothelioma.
Patients will be adults who have histologically confirmed malignant abdominal mesothelioma and will have received 0-2 prior chemotherapeutic regimens. Referral from the consultation service may take place only with the agreement of the responsible attending physician.

All patients will undergo exploratory laparotomy. An attempt will be made to remove all nodules of greater than 1 cm in diameter. Approximately three to four weeks following surgery, intraperitoneal chemotherapy will be initiated weekly for twelve weeks. Following the intraperitoneal chemotherapy, patient will receive intraperitoneal immunotherapy weekly for four weeks.

Afterward, patients will undergo a second operation similar to first, where the abdomen will be re-inspected for any remaining or re-growing tumor. A single treatment with heated chemotherapy drugs (cisplatin/mitomycin) will be washed through the abdominal cavity for 90 minutes and the port-a-cath will be removed. If tumor remains in the abdomen after these treatments, patients will be removed from the study.

Patients will then receive 5 weeks of radiation therapy (Monday through Friday) directed to the whole abdomen. This will complete the treatment.

Patient Inclusion/Exclusion Criteria:

Prior therapy allowed:

0-2 prior chemotherapy regimens; greater than 6 weeks since chemotherapy
Greater than 1 week since surgery (prior surgical resection preceding disease recurrence is acceptable)
No prior abdominal or lower chest radiation therapy
Non pregnant, non lactating

Clinical Parameters:

Life expectancy greater than 2 months
Age greater than 18 years
Performance status 0-2 (SWOG)
Required initial laboratory data:

White cell count greater than 3000/ul
Platelet count greater than 100,000/ul
Calculated creatinine clearance greater than or equal to 45 ml/min
Bilirubin less than 1.5 x normal
Dr. Robert Taub is the Principal Investigator.

Transgene begins new phase ii gene therapy trial in mesothelioma

STRASBOURG, Mar 11 (Reuters Health) – The biotechnology company Transgene announced Wednesday that it is launching a new phase II trial of its Vero-IL2 product for the treatment of mesothelioma. The trial will involve a total of 20 patients with advanced mesothelioma.

Vero-IL2 comprises an immortal cell line genetically modified to produce interleukine-2, Transgene said in a statement. Animal tests demonstrated the effectiveness of the product in the treatment of spontaneous tumours, and two phase I clinical trials carried out in France and Switzerland indicated antitumor activity with good tolerance to the treatment.


The first phase II trials, in the treatment of advanced melanoma, started in the spring of 1998. "We are pleased to continue the development of this product for the mesothelioma indication, a disease for which no treatment exists at this stage." general manager Bernard Gilly commented. "This new trial brings to four the number of phase II clinical trials for the treatment of various cancers in progress at Transgene."


-Westport Newsroom 203 319 2700

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Transgene begins new phase ii gene therapy trial in mesothelioma

STRASBOURG, Mar 11 (Reuters Health) – The biotechnology company Transgene announced Wednesday that it is launching a new phase II trial of its Vero-IL2 product for the treatment of mesothelioma. The trial will involve a total of 20 patients with advanced mesothelioma.

Vero-IL2 comprises an immortal cell line genetically modified to produce interleukine-2, Transgene said in a statement. Animal tests demonstrated the effectiveness of the product in the treatment of spontaneous tumours, and two phase I clinical trials carried out in France and Switzerland indicated antitumor activity with good tolerance to the treatment.


The first phase II trials, in the treatment of advanced melanoma, started in the spring of 1998. "We are pleased to continue the development of this product for the mesothelioma indication, a disease for which no treatment exists at this stage." general manager Bernard Gilly commented. "This new trial brings to four the number of phase II clinical trials for the treatment of various cancers in progress at Transgene."


-Westport Newsroom 203 319 2700

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Phase II Trial Of Pemetrexed In Malignant Pleural Mesothelioma (MPM) Patients: Clinical Outcome, Role Of Vitamin Station, Respiratory Symptoms Upplemenand Lung Function

Reviewer: Heather Jones, MD
The University of Pennsylvania Cancer Center
Posting Date: May 22, 2002

Presenter: Dong M Shin,
Presenter’s Affiliation: University of Pittsburgh
Type of Session: Scientific
Background


Malignant pleural mesothelia (MPM) is generally caused by exposure to asbestos and is commonly accompanied by pleural effusion, sometimes making radiologic images difficult to interpret. As the worldwide incidence of MPM increases, few chemotherapeutic agents have demonstrated more than modest activity. Pemetrexed, a novel multi-targeted antifolate that inhibits thymidylate synthase and other folate-dependent enzymes, has been demonstrated to have activity in a wide variety of tumors. Supplementation of folate and vitamin B12 has been shown to reduce toxicity associated with pemetrexed. The objective of this phase II study of pemetrexed in patients with advanced MPM included evaluating tumor respone rate (RR), time to progression (TTP) median survival (MS), and toxicity.
Materials and Methods


64 chemotherapy-naive patients received pemetrexed, 500 mg/m2 (10 min IV infusion day 1) every 21 days
Low-dose folic acid (FA) and vitamin B12 (B12) were added during the study as this has been shown to reduce grade (G) 3/4 toxicities
43 patients were fully supplemented (received FA/B12 throughout)
21 patients were non-supplemented (never received FA/B12 )
Results


Fully supplemented patients completed a median of 6 cycles; RR:16%; median TTP:4.8 months (mos); MS:13 mos.
Non-supplemented patients completed a median of 2 cycles; RR: 9.5 %; median TTP:3 mos; MS: 8 mos. G3/4 hematological toxicities for fully supplemented group were neutropenia (4.7/4.7%), leukopenia (9.3/0%), thrombocytopenia (2.3/0%), respectively compared to non-supplemented patients – neutropenia (14.3/ 38.1 %), leukopenia (28.6/9.5 %) and thrombocytopenia (1.6/1.6 %)
No significant non-hematological toxicities were reported
On the Lung Cancer Symptom Scale pt scale, responders noted improvement in anorexia, fatigue, dyspnea, pain, symptom distress, activity level and global QoL.
On the LCSS observer scale, 63% of responders were rated as improved in total score.
Patients who responded to treatment showed an increase in lung volume and motility.
Author’s Conclusions


This study demonstrates promising activity and good tolerability of pemetrexed in patients with mesothelioma. Vitamin supplementation resulted in a marked decrease in the amount of grade 3/4 hematologic toxicity without reducing the clinical efficacy of pemetrexed.
Clinical/Scientific Implications


Despite many trials with numerous regimens, none of these combination chemotherapy regimens have consistently yielded response rates higher than those seen in single-agent studies. The development and testing of newer agents for the treatment of malignant pleural mesothelia are clearly needed. These are early results, yet the responses and dramatic reduction of toxicity in the patients receiving ALIMTA and folic acid are encouraging. Future clinical trials should be carried out to define the role that this drug will play in the treatment of malignant pleural mesothelia.

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Phase III single-blinded study of premexetred + cisplatin vs. cisplatin alone in chemonaive patients with malignant pleural mesothelioma

Reviewer: Ryan Smith, MD
The University of Pennsylvania Cancer Center
Posting Date: May 19, 2002


Presenter: N.J. Vogelzang
Presenter’s Affiliation: U of Chicago
Type of Session: Plenary
Background


Mesothelioma is an aggressive malignancy with no consistent, proven benefit to any traditional treatment: surgery, radiation therapy, or any combination of chemotherapy. Premexetred is an anitfolate, targeting key enzymes in the purine and pyrimidine synthesis that has shown efficacy in phase I data. This is a phase III study randomizing patients to premexetred and cisplatin (PC) vs. cisplatin alone (C).
Materials and Methods


472 patients entered the study. 452 were randomized, with 448 eligible for analysis.
All had unresectable mesothelioma, well-balanced with respect to KPS, gender, and histology.
All patients analyzed had at least 1 cycle of chemotherapy with a minimum follow up of 9 months
Arm A-Premexetred 500 mg/m2 over 10 minutes followed 30 minutes later by cisplatin 75 mg/m2 delivered every 3 weeks
Arm B-Ciplatin 75 mg/m2 alone every 3 weeks
As enrollment reached close to 150 patients, it was noted that there was a high rate of death and severe toxicity due to febrile neutropenia and diarrhea in the PC group. Investigation linked these toxicities to increased homocysteine and methylmalonic acid levels
After this toxicity was noted, the remainder of patients in both groups received folic acid (350-1000 mcg) q day and vitamin B12 (1000 mcg)q 9 weeks beginning 21 days prior to chemotherapy
Distribution of patients: Pre-vitamin supplementation-PC=58 patients, C=59 patients. After vitamin supplementation-PC=168, C=163. Total was PC=226 patients, C=222 patients
Results


MST (total): PC=12.2 mo, C=9.3 mo (p=.02). MST (supplemented patients): PC=13.3 mo, C=10.1 mo (p=.05)
Time to progression (total): PC=5.7 mo vs. C=3.9 mo (p=.001). Time to progression (supplemented patients): PC=6.1 mo vs. C=3.9 mo (p=.008)
Risk reduction (total): PC=44% vs. C=17%. Risk reduction (supplemented patients): PC=46% vs. C=20% (p<.001)
Median cycles of chemotherapy delivered was 2 in the non-supplemented patients vs. 6 in the supplemented patients
There was a 28% rate of severe neutropenia in the PC group, though it decreased from 41% to 23% with supplementation
Severe nausea and vomiting decreased from 21% to 11% with supplementation
Lung function began improving with the start of the 2nd cycle of chemotherapy. There was more extensive improvement in the PC group. This objective improvement translated to a subjective improvement in patients’ dyspnea.

There was a significant improvement in survival, TTP, RR, lung function, and subjective indicators of quality of life
There was a reduction in toxicity with supplementation with folic acid and vitamin B12
This should be considered standard chemotherapy in mesothelioma
Clinical/Scientific Implications

Mesothelioma has been a frustating disease to treat, as there has been no therapy that has consistently improved the outcome in patients. This study shows a definite improvement in survival, TTP, and RR with PC chemotherapy. Therefore, this should be the standard chemotherapy used, as it supercedes the results with all single agent chemotherapies, and is likely better than the recently popular gemcitabine and cisplatin. However, the toxicity is moderate, with the MST still around 1 year. Therefore, patients should be selected carefully to undergo this therapy. Also, investigations should continue to be made into different chemotherapy regimens. In addition, experimental treatments should continue to be investigated, as survival even with this improved regimen is low. Again, although there is evidence of symptom improvement with this regimen, the potential toxicity should still be weighed against the relatively short life span of most of these patients.

 


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