Tamibarotene

Tamibarotene (formerly known as TM-411, TOS-80T, Am-80, and INNO-507) is an orally available, rationally designed, synthetic retinoid compound which was designed to potentially avoid toxic side effects by binding to its molecular target more selectively than all trans-retinoic acid (ATRA), the current first line treatment for APL.

Non-Small-Cell Lung Cancer

In December 2010, CytRx initiated a Phase 2b clinical trial in patients with advanced non-small-cell lung caner (NSCLC). In this randomized clinical trial, patients with advanced NSCLC are treated with paclitaxel plus carboplatin and either tamibarotene or placebo. The primary objective of this trial is to determine the objective response rate (complete and partial responses) and progression-free survival. Secondarily, the trial will evaluate overall survival, quality-of-life and examine the pharmacokinetics of tamibarotene in this population, among other measures.

A clinical trial conducted by Arrieta et al. and published in the peer-reviewed Journal of Clinical Oncology (June 17, 2010)compared ATRA added to a regimen of paclitaxel plus cisplatin to a regimen of paclitaxel plus cisplatin alone as a treatment for patients with advanced NSCLC. The group administered ATRA plus the chemotherapeutical agents showed improved response rates of 55.8% versus 25.4%, and increased progression-free survival of 8.9 months versus 6.0 months. Median overall survival was increased from 9.5 months to 23.5 months when ATRA was added to the above chemotherapy regimen, representing a 14-month median extension of life.

Human Clinical Trial

A First Line Study of Tamibarotene in Combination for Advanced Non-Small Cell Lung Cancer is ongoing. Click on the following link for current clinical trial information and eligibility criteria: clinicaltrials.gov

APL

Acute promyelocytic leukemia (APL) is a subtype of acute myelogenous leukemia, a cancer of the blood and bone marrow. In APL, an abnormal accumulation of immature granulocytes called promyelocytes in the bone marrow results in a reduction in the production of normal red blood cells and platelets, resulting in anemia and thrombocytopenia. Either leukopenia (low white cell count) or leukocytosis (high white cell count) may be observed in the peripheral blood. Symptoms include fatigue, weakness, shortness of breath from anemia, easy bruising and bleeding from thrombocytopenia and coagulopathy, and fever and infection from lack of normal white blood cells.

All-trans retinoic acid (ATRA) is the current standard of care for first-line treatment of APL in combination with chemotherapeutic agents. ATRA can cause differentiation of abnormal promyelocytes into mature granulocytes in APL. ATRA has been associated with retinoic acid syndrome, a serious and sometimes fatal complication that occurs in up to 25% of patients due to a rapid increase in white blood cells. Current National Comprehensive Cancer Network guidelines also recommend that patients undergo one to two years of maintenance therapy with ATRA following disease remission.

Tamibarotene was developed to specifically overcome resistance to ATRA. In vitro, tamibarotene is approximately 10 times more potent than ATRA at causing APL cells to differentiate and die. In addition, tamibarotene has a lower affinity for cellular retinoic acid binding protein, or CRABP, which we believe should allow for sustained plasma levels during administration. Tamibarotene does not bind the RAR-gamma receptor, the major retinoic acid receptor in the dermal epithelium. In clinical studies, the rate of RAS appeared to be low.

Tamibarotene is currently approved in Japan for treatment of recurrent APL. There is a Special Protocol Assessment (SPA) in place with the FDA for a Phase 2 clinical trial, known as STAR-1, which is evaluating the efficacy and safety of tamibarotene as a third-line treatment for APL. CytRx reported that, of the 11 patients enrolled in the STAR-1 trial to date, three (27%) achieved a hematologic complete response, and four (36%) a morphologic leukemia-free state. CytRx holds the North American and European rights to tamibarotene as a treatment for APL.

The FDA has granted Orphan Drug Designation for APL and Fast Track Designation for the use of tamibarotene in patients with relapsed or refractory APL following treatment with all-trans retinoic acid (ATRA) and arsenic trioxide. In addition, tamibarotene has been granted orphan medicinal product status by the European Medicines Agency for the treatment of APL. The efficacy of orally-administered tamibarotene was demonstrated in two Phase 2 studies conducted in Japan in a total of 63 Japanese subjects with APL. The overall complete response rate in these subjects was 60%. In subjects experiencing their first relapse, the overall complete response rate was 81%.

Human Clinical Trial

A Phase 2 Registration Study of Oral Tamibarotene in Acute Promyelocytic Leukemia Patients Who Have Received Prior Therapy with ATRA and Arsenic Trioxide (STAR-1) is ongoing.

Click on the following link for current clinical trial information and eligibility criteria: clinicaltrials.gov

Other Indications

Tamibarotene has also showed statistically significant anti-tumor activity in animal trial for multiple myeloma, an incurable malignant tumor of the plasma cells of bone marrow. CytRx retains an option to expand its licenses for the use of tamibarotene in other fields in oncology, including multiple myeloma, myelodysplastic syndrome and certain solid tumors in the U.S., and multiple myeloma, myelodysplastic syndromes and solid tumors other than hepatocellular carcinoma in Europe.