ET 743 (Ecteinascidin) promising cancer drug

ET-743 (ECTEINASCIDIN)

ET-743 (Ecteinascidin) is the first and one of the most promising drugs in PharmaMar's pipeline. ET-743 is a compound obtained from the tunicate Ecteinascidia turbinata sea squirts that live in clusters in the Caribbean and Mediterranean seas. Tunicates are sea creatures encased by tough membranes, reminiscent of tunics. PharmaMar synthesizes ET-743 at its facilities in Madrid, Spain.

Early trial results have indicated that ET-743 may eventually play a role in treating certain soft tissue sarcomas and other cancers. Anti-tumor activity was observed in all Phase I studies, which were conducted on patients with advanced-stage breast, colon, ovarian and lung cancer, melanoma, mesothelioma and several types of sarcoma (cancer arising in connective tissue such as muscle or bone). ET-743 showed particularly high activity in cases of advanced sarcoma that had relapsed or were resistant to conventional therapy. Sarcoma is an indication where there is a lack of effective solutions. These results are expected to open the door to an accelerated registration process for the drug.

Phase I trials also showed that a short treatment schedule for ET-743 (three-hour infusions every three weeks) was feasible a finding of great significance since it will facilitate outpatient administration of the drug.

Phase II clinical trials were launched in February 1999, with patients with advanced, therapy-resistant disease, including sarcoma, osteosarcoma, and breast, non-small lung, and ovarian cancer.

To date, a total of 505 patients have been treated with ET-743.

Researchers believe that several unique characteristics of ET-743 distinguish it from known DNA-interacting drugs. The ET-743 molecule, which consists of three domains or rings, binds to the minor groove of the DNA double helix, with two of the rings making close contact with the double helix and forming a linkage to a guanine, one of the four bases of the DNA. In this complex, the DNA double helix bends toward the major groove and the third ring of ET-743 positions itself outside the complex, exposed to the cellular environment. This third ring is available to interact with proteins, and this might explain the unique effects of the drug. Among these is the capacity of ET-743 to block the induction of the MDR1 gene, which encodes a membrane pump involved in the resistance that tumor cells often acquire to multiple drugs.

Key facts about Phase II Trials of ET-743 (ECTEINASCIDIN) in three distinct patient groups with Sarcoma G. DEMETRI, ET AL Phase II clinical trial results for ET-743 in sarcoma

Forty-seven percent (14 of 30) of patients with advanced soft-tissue sarcomas who had received one or two prior chemotherapy regimens have exhibited stable disease or objective response (tumor shrinkage by more than half of the pretreatment size).
Forty-seven percent (eight of 17) of patients with advanced soft-tissue sarcoma patients with no prior chemotherapy (first-line study) have exhibited stable disease or objective response.
In patients with a notoriously difficult-to-treat sarcoma known as gastrointestinal stromal tumor (GIST), only 6 percent (one of 18) have responded.
Preliminary evidence of clinical activity has been observed in liposarcoma, leiomyosarcoma and synovial sarcoma.

Phase II clinical study design

Primary objective: to assess the activity of ET-743 in three distinct groups of patients with sarcomas.
Three coordinated U.S.-based studies patient accrual:
- 30 patients with advanced soft-tissue sarcomas who had received one or two prior chemotherapy regimens
- 17 patients with advanced soft-tissue sarcoma patients with no prior chemotherapy
- 18 patients with gastrointestinal stromal tumor (GIST)
Dosage and schedule: 1,500 µg/m2 by 24-hour continuous IV infusion on an outpatient basis, repeated in cycles of three to four weeks.
Patients were restaged after every two cycles.
Pharmacokinetics of ET-743 monitored in all patients during the first cycle of therapy to assess interpatient variability and possible correlations between pharmacokinetics and clinical activity or toxicity. Summary of adverse events reported in the Phase II study
Tolerability of ET-743 treatment has been very good.
Nausea was eliminated by incorporating dexamethasone as a prophylactic antiemetic regimen. Other toxicities included myelosuppression, temporary and asymptomatic transaminitis, and fatigue.

Summary

ET-743 is an extremely promising agent for the management of several histologic subtypes of soft tissue sarcoma. Regulatory status: ET-743 is currently in Phase II clinical trials.

The ET-743 molecule, which consists of three domains or rings, binds to the minor groove of the DNA double helix, with two of the rings making close contact with the double helix and forming a linkage to a G base of the DNA. In the ET-743 DNA adduct, the double helix bends toward the major groove and the ring of ET-743 positions itself outside the complex. This third ring is available to interact with proteins, and this might explain the unique effects of the drug.

ET-743 by inhibits induction of the MDR1 gene, responsible for multiple drug resistance. These characteristics are unique to ET-743 and distinguish it from all known DNA-interacting drugs.

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