Posting parts of an old release I found through Henry's website. Here encouraging results are reported in regard to stabilization of lung cancer by Targretin in P1/2 trials. We should be hearing results from the P2/3 Targretin NSCLC soon. I have posted mostly for the toxicity information in regard to Targretin. All things considered toxicity looks awfully good compared to chemotherapeutics. The two studies seemed to differ on dose limiting toxicities, one finding no limitation at 650mg/m2/day and another finding a limit at 400mg/m2/day. Squetch, it appears from this release that m2 refers to square meter of body surface.
>>Ongoing Phase I-IIa Clinical Trial Results for Ligand Retinoid Product, LGD1069, Presented at AACR and NCI-EORTC Meetings
WASHINGTON, April 25 /PRNewswire/ via Individual Inc. -- In two recent studies, clinical investigators evaluating Targretin(TM) (LGD1069) Oral capsules in patients with advanced cancers have reported stabilization of disease in many of their patients with non-small cell lung cancer (NSCLC). Investigators from the Vincent T. Lombardi Cancer Center at Georgetown University Medical Center (Georgetown) reported eight of 15 lung cancer patients with stable disease in excess of three months. Investigators at Memorial Sloan Kettering Cancer Center reported that eight of 20 lung patients demonstrated stabilization of disease for three to eight-plus months.
Georgetown investigators reported results of an ongoing Phase I-IIa human clinical trial on Targretin (LGD1069) Oral at the annual meeting of the American Association for Cancer Research (AACR) in Washington Tuesday.
"With this class of compounds, we would consider stabilization of disease an important clinical parameter," according to Michael Hawkins, M.D., Associate Professor of Medicine and Director of Experimental Therapeutics, Division of Hematology and Oncology, Lombardi Cancer Center. "Of the 15 patients with non-small cell lung cancer, disease stabilization was observed for up to 394 days. Up to the 650 mg/m2/day dose level, stabilization was observed for a mean of 132 days, suggesting Targretin may have stabilized disease in this population. Targretin was extremely well tolerated with little toxicity observed."
There are two distinct subfamilies of retinoid receptors: RARs and RXRs, which appear to have different functions. Targretin (LGD1069), a proprietary retinoid product discovered and under development by Ligand Pharmaceuticals Inc. (Nasdaq: LGND) is the first RXR-selective retinoid in clinical development. These investigators reported that unlike previous retinoids, Targretin (LGD1069) Oral primarily induces programmed cell death (apoptosis) in tumor cell lines which may make it particularly interesting for the treatment of certain slow-growing cancers.
The Phase I-IIa trial at Georgetown is a dose escalation study designed to evaluate tolerability, safety and pharmacokinetics in patients with advanced cancer of various types.
The Georgetown team reported on 50 patients with various forms of cancer treated as long as a year or more with Targretin(TM) (LGD1069) Oral at once daily doses ranging from 5 to 800 mg per square meter of body surface (mg/m2). The investigators reported that dose limiting toxicity was observed in one patient with skin desquamation at the 650 mg/m2 dose level and one patient with a clotting disturbance (prothrombin time elevation) at the 230 mg/m2 dose level.
The investigators reported that at daily doses up to 140 mg/m2, Day 15 area under the curve (AUC) levels were similar to Day 1 values, suggesting that Targretin did not induce its own metabolism as a result of repetitive daily dosing. Investigators have said that this finding suggests that Targretin (LGD1069), unlike some retinoids, may be suitable for chronic administration at therapeutically useful doses. AUC levels are a measure of exposure to drug. At higher doses, plasma Targretin concentrations decreased following repeat administration.
CONCLUSIONS OF THE GEORGETOWN STUDY
The conclusions reported by Georgetown investigators at AACR were the following.
1. Targretin (LGD1069) Oral was extremely well-tolerated with little toxicity observed. Skin reaction (cheilitis, xeroderma, peeling) is a frequent complication of RAR-selective and pan-agonists, however it was minimal with Targretin. Other dose-limiting toxicities seen with previous retinoids (headache, hypercalcemia) that have been dose limiting were not seen with Targretin.
2. No objective tumor regression was observed. However, selected patients, including patients that had progressed after prior therapies, had stabilization of disease for extended periods.
3. Plasma Targretin concentrations increased dose proportionally. Above 140 mg/m2, they exceeded the IC50 in cell lines suggesting that effective concentrations may be clinically achieved.
4. In this Phase I study, dose limiting toxicity has not been established, and patients continue to be accrued.
5. Targretin is a novel, RXR-selective, synthetic retinoid agonist that may have a favorable therapeutic index and merits further clinical investigation.
Results on Targretin(TM) (LGD1069) Presented at the NCI-EORTC Meeting
Investigators from the Memorial Sloan Kettering Cancer Center (MSKCC) reported results of a closed Phase I-IIa human clinical trial of Targretin(TM) (LGD1069) Oral at the 9th National Cancer Institute (NCI) and European Organization for Research and Treatment of Cancer (EORTC) Symposium on New Drugs in Cancer Therapy held in March.
"Of 20 lung cancer patients treated with Targretin, eight have demonstrated stabilization of disease for three to over eight months," according to James Rigas, M.D., formerly of MSKCC, now Assistant Professor of Medicine at Dartmouth Medical School.
The MSKCC team treated 52 patients with various forms of cancer with Targretin (LGD1069) Oral at once daily doses ranging from 5 to 500 mg per square meter of body surface (mg/m2). The 22 female and 30 male patients in the study had a median age of 56 (range 25-82), and their diagnoses included NSCLC (20) cutaneous T-cell lymphoma (CTCL) (9), adenoid cystic carcinoma (7), and other tumor types (16).
These investigators reported that pharmacokinetic sampling performed on days 1, 15 and 29 on 27 patients at 8 dose levels using a sensitive assay revealed that plasma concentrations of drug are approximately dose proportional with no evidence of induction of metabolism at repetitive doses up to and including 400 mg/m2/day. The dose limiting toxicity in this study was reversible elevation of serum transaminase levels at 400 mg/m2/day.
Characteristically severe retinoid toxicities such as headache, arthralgias, and mucocutaneous toxicity were reported to have been uncommon. Other adverse effects have included rash and occasional dose- related, low- grade leukopenia/neutropenia (reduction in white blood cells).
Two of nine patients with CTCL experienced a major improvement; eight of twenty patients with metastatic NSCLC and three of seven with adenoidcystic carcinoma have demonstrated clinically meaningful stabilization of disease for three to eight-plus months.
Conclusions of MSKCC Study
The conclusions reported by MSKCC investigators at the NCI-EORTC were the following.
1. Selective RXR activation yields a pattern of biological activity different from that of RAR, selective-agonists, such as Vesinoid(R) (all- trans retinoic acid), or pan RAR/RXR-agonist ligands, such as ALRT1057 (9- cis retinoic acid).
2.Targretin (LGD1069) Oral was generally well-tolerated.
3. Dose limiting adverse events were reported to be reversible transaminase elevations at 400 mg/m2/day. Hypercalcemia (NCI grade III) was observed at 500 mg/m2/day.
4. Characteristic retinoid toxicities such as headache, arthralgias, and mucocutaneous toxicity were mild to absent.
5. Other adverse effects have included rash and occasional dose- related, low-grade leukopenia/neutropenia (reduction in white blood cells).
Ligand intends to pursue further studies to explore Targretin (LGD1069) Oral as a maintenance therapy in NSCLC and a synergistic agent with cytotoxic therapy in NSCLC. Targretin (LGD1069) Oral Phase IIb trials have begun in kidney cancer (in combination with interferon alpha), and head and neck cancer with plans to enter prostate and ovarian cancer this year. Targretin (LGD1069) Topical gel is being evaluated in a Phase I-II trial patients with CTCL.
Ligand Pharmaceuticals Incorporated, founded in 1987, is a leader in gene transcription technology, particularly intracellular receptor (IR) technology and Signal Transducers and Activators of Transcription (STATs). Ligand has applied IR and STATs technology to the discovery and development of small molecule drugs to enhance therapeutic and safety profiles and to address major unmet patient needs in cancer, women's health, skin diseases, osteoporosis, cardiovascular and inflammatory disease. |
