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.

 

Unfortunately, the duration of remission induced by treatment with ATRA alone is typically short. In addition, patients often fail to respond to a second course of treatment with ATRA. Currently, patients who fail ATRA-based therapy are treated with arsenic trioxide, a compound administered intravenously and associated with significant toxicity including irregular heartbeat. There is no standard of care for patients who do not respond to ATRA and arsenic trioxide.

 

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. The STAR-1 trial is ongoing and currently includes six clinical sites in the U.S.  CytRx recently 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. Based on the preliminary results in the clinical trial for third-line APL, CytRx has announced its intention to work with key opinion leaders to design a clinical trial to evaluate tamibarotene in combination with other agents as a first-line treatment for this cancer. 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%.

 

APL is diagnosed in approximately 1,500 new patients in the United States annually. The near-term market opportunity for CytRx’s tamibarotene in refractory APL in the U.S. alone is estimated to approach $20 million per year - with the market opportunity for an expanded label including refractory, maintenance and front-line therapy increasing to $150 million in potential recurring revenue in the U.S. and Europe. There are currently no approved third-line treatment options for refractory APL patients.

 

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.

 

CytRx plans to initiate a clinical trial to develop its oncology drug candidate tamibarotene in combination with chemotherapy or arsenic trioxide (ATO) as a first-line treatment for APL. In addition, a dose escalation study with tamibarotene combined with arsenic trioxide injection in patients with relapsed APL is currently being conducted by Northwestern University under the leadership of Dr. Martin Tallman, Professor of Medicine, and Dr. Jessica Altman, Assistant Professor of Medicine, both at the Northwestern University Feinberg School of Medicine. In this multi-center Phase 1 trial, between 16 and 22 relapsed APL subjects in three dose groups will be treated with two to three six-week cycles of intravenous arsenic trioxide and self-administered oral tamibarotene tablets with two to six weeks between cycles. A total of 10 subjects will be enrolled at the maximum dose for one or two additional cycles of therapy and evaluated for disease remission. The dose for the subsequent Phase 2 trial will be the dose at which at least five of six subjects tolerate the treatment or the maximum dose used in this trial.

 

Human Clinical Trials
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 link below for current clinical trial information and eligibility criteria:

clinicaltrials.gov

 

Bibliography
Tadasu Tobita, Akihiro Takeshita, et al. Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. BLOOD, 1 August 1997;VOLUME 90, NUMBER 3