Tretinoin Liposomal

Atragen® | Atragen®

Investigational

Classification:
Antineoplastic Agents

• Retinoids

Comments:

Description: A liposomal-encapsulated IV form of tretinoin is undergoing clinical investigation for a variety of leukemias and soft-tissue cancers. Tretinoin or all-trans-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A.

Actions: similar to oral tretinoin (Vesanoid®); retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction; tretinoin binds to all three RARs (alpha, beta, and gamma), but does not bind to RXRs except at very high concentrations; recently it was determined that tretinoin down-regulates the expression of bcl-2.

Uses: under investigation for the treatment of acute promyelocytic leukemia (APML), acute myeloid leukemia (not APML), Kaposi’s sarcoma, hormone-refractory prostate cancer, relapsed T-cell and B-cell non-Hodgkin’s lymphoma (NHL), and cutaneous T-cell lymphoma (CTCL), aka mycosis fungoides. In a phase II study of APML patients, the complete remission rate for newly diagnosed patients was 87% and 55% for patients with relapsed or refractory disease. However, in patients refractory to oral tretinoin, the response rate was < 25%. Data from an on-going phase II trial in patients with relapsed or refractory NHL or CTCL has shown overall response rates (complete plus partial responses) of 38 - 40% in patients refractory B-cell and T-cell lymphomas. In patients with relapsed B-cell and T-cell lymphomas, the overall response rates were 8% and 27%, respectively.

Distinguishing Features: longer half-life compared to tretinoin due to ability to circumvent liver metabolism and no induction of liver enzymes; more activity against lymphoma cell lines than oral formulation.

Major Adverse Reactions: similar to tretinoin; arthralgia, headache; dry skin.

Usual Adult Dosage: In acute promyelocytic leukemia 90 mg/m2/day IV every other day until complete remission or for a maximum of 56 days. In patients with relapsed or refractory NHL or CTCL, 120 mg/m2 IV every other day for 28 days for up to 6 courses has been used. In a phase I/II trial of Kaposi’s sarcoma, doses studied were 60, 90, or 120 mg/m2/week in 3-divided doses given 3 days a week.

Status: In January 2001, the FDA denied approval of the NDA for acute promyelocytic leukemia; the principle deficiency in the NDA identified by the FDA was that the data do not establish an identifiable population of patients who cannot take the oral formulation. Regulatory filing in Europe for Atrogen® in the treatment of APL is planned. The company plans on continuing clinical development in other indications; expanded trials in non-Hodgkin’s lymphoma and hormone-resistant prostate cancer are planned.

Manufacturer: Aronex Pharmaceuticals, The Woodlands, Texas.
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