At the 2009 meeting of the American Society of Clinical Oncology (ASCO) there were several preclinical and Phase I-II clinical presentations suggesting activity for a new inhibitor of the Bcl-2 family of proteins (Bcl-2, Bcl-xL, Mel-1, Bcl-W), AT-109, developed by Ascenta Therapeutics.

Bcl-2 derives its name from B-cell lymphoma. The Bcl-2 family is a group of proteins that are present in a number of cancers, including melanoma, breast, prostate, and lung carcinomas; these proteins are thought to be involved in resistance to conventional cancer treatment by interfering with apoptosis. There are no Bcl-2 inhibitors approved by the U.S. Food and Drug Administration. The best studied is Genasense® (Genta Incorporated), which is probably close to approval for the treatment of chronic lymphocytic leukemia (CLL). Another small molecule Bcl-2 inhibitor, GX15-070, has been developed by Gemin X and has also shown activity in refractory CLL.

AT-101 is a small molecule inhibitor of the Bcl-2 family, which increases apoptosis in a variety of tumor cell systems and appears to have broad clinical activity. AT-101 is administered orally and appears to be well tolerated as a single agent or in combination with chemotherapeutic agents. Development of this drug has reached Phase II testing; several Phase I-II studies were reported at ASCO 2009.

Researchers from the University of Wisconsin presented the results of a Phase I clinical trial of AT-101 and Platinol® (cisplatin) and Vepesid® (etoposide) plus or minus Neulasta® (pegfilgrastim) in 10 patients with solid tumors, including small cell lung cancer (SCLC).[1] This study established a tolerable dose for Platinol, Vepesid, and AT-101 without Neulasta, but the MTD with Neulasta has not been reached. The study is still accruing patients.

Researchers from the United States and Russia reported that the combination of AT-101 and Taxotere® (docetaxel) was well tolerated as second-line therapy in patients with non–small cell lung cancer (NSCLC).[2] This study also included testing for a genomic predictor of sensitivity to AT-101 and included 106 patients who were randomly allocated to receive Taxotere alone or Taxotere with AT-101. Median overall survival (OS) was 7.3 months for the AT-101 group and 5.6 months for the Taxotere alone group. The median progression-free survival (PFS) was 12.6 weeks for the AT-101 group and 10.7 weeks for the control group. The only side effect attributable to AT-101 was headache. These authors also reported that response was predicted by the 500 gene study.

Researchers in the United States affiliated with NABTT (New Approaches to Brain Tumor Therapy) trial number 0702 reported that AT-101 was well tolerated with possible activity in patients with recurrent glioblastoma multiforme.[3] All had received prior radiation therapy, and none had received more than two prior therapies. Patients receive AT-101 for 21 of 28 days with repeat courses until disease progression. This study included 56 patients. Seven patients had stable disease, and there was one partial response. Two patients were without progression at seven months. These authors suggested that AT-101 was well tolerated and longer follow-up would determine possible effects on survival.

Researchers from several U.S. medical centers reported the results of treating 23 patients with untreated follicular lymphoma (FL) who did not require immediate treatment with the combination of AT-101 and Rituxan® (rituximab).[4] Patients received four weekly induction courses of AT-101 and Rituxan followed by maintenance therapy every eight weeks in responders. All patients received induction therapy, and 18 received maintenance therapy. The overall response rate was 70% with 4% achieving a complete response. The dose of AT-101 had to be reduced in this study due to GI intolerability. It was not clear from this study whether or not AT-101 improved the response rate over what would have been expected with Rituxan alone. These authors stated that a randomized trial would be necessary to determine the added benefit of AT-101.

A Phase I-II trial of AT-101 and Hycamtin® (topotecan) in patients with relapsed or refractory SCLC was reported by U.S. researchers.[5] In this study response rates did not meet the criteria for expanded Phase II enrollment. However, these researchers suggested that many patients responded better than historical controls and that further studies in SCLC were indicated.

Researchers from Upstate Medical University, Florida Cancer Specialists, and Hanover Medical Specialists reported that AT-101 could be give safely with Taxotere and prednisone in men with advanced prostate cancer who had failed prior therapy with Taxotere.[6] This study included 40 patients who had progressive disease while receiving Taxotere. All received Taxotere and prednisone with AT-101 given on days 1-3 of each 21-day cycle of therapy. Thirty-five percent of patients had at least a 30% reduction in PSA levels and 18% had at least a 50% reduction in PSA levels. Twenty-four percent of evaluable patients had a PR or CR by RECIST criteria. Fifteen patients remain on study, and three have received therapy for six or more months. These are convincing data for activity of AT-101 in prostate cancer.

Researchers from Northwestern University, the Sarah Cannon Cancer Center, and Florida Cancer Specialists presented the results of a Phase I/II study of AT-101 in combination with Taxotere and prednisone in men with castrate-resistant prostate cancer (CRPC).[7] This study included 36 men with CRPC who were treated with Taxotere, prednisone, and AT-101. AT-101 was given twice daily on days 1-3 of each 21-day cycle of treatment. Sixty-seven percent of men in this study achieved at least a 50% reduction in PSA levels. Seventy-two percent had at least a 30% decrease in PSA levels. Forty-seven percent of 19 men with measurable disease had a partial response. A reduction in circulating tumor cells was also detected and this predicted response. Serious side effects were not thought to be increased over that expected with Taxotere and prednisone without AT-101. These authors stated that a Phase III trial was ongoing to confirm activity of AT-101 in prostate cancer.

Comments: These studies, taken together, suggest significant activity of AT-101 when combined with other agents for the treatment of several types of cancer. Prostate and NSCLC appear to be the most promising. However, given the relative long history of Genasense without FDA approval, it may be some time before AT-101 is approved.

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