Alisertib-Based Combo Improves Survival Outcomes in Ovarian, Breast Cancer

In Clinical Trials by Barbara Jacoby

By: Jessica Skarzynski

From: curetoday.com

For some time now, paclitaxel has been considered standard of care in the treatment of patients with platinum-resistant ovarian cancer; however, recent research has shown the addition of the investigational drug alisertib to a paclitaxel regimen demonstrated promising activity in patients with recurrent ovarian cancer or advanced breast cancer.

In the JAMA Oncology study, the researchers noted that alisertib has shown modest single-agent activity in patients with platinum-resistant ovarian and breast cancer, and is generally well tolerated. Given that, and the fact that the combination of alisertib and paclitaxel showed promise in preclinical trials, Falchook and his colleagues conducted a multicenter, open-label phase 1/2 study to evaluate the drug combination in both patient populations.

Phase 1, which ran from May 2010 to August 2012, included 49 patients with either recurrent ovarian or breast cancer from 33 sites in the US, France and Poland. In addition to determining the tolerability and recommended dosage of the drug combination for phase 2, the researchers also evaluated overall response rate, duration of response, time to progression and overall survival as secondary endpoints.

Patients received the two drugs concurrently, which included 10 mg of alisertib orally mg twice daily on days 1 through 3, 8 through 10 and 15 through 17 in 28-day cycles; and while researchers monitored the effects in the first cycle, the alisertib doses were increased twice daily in 10-mg increments until the maximum tolerated dose was reached.

Additionally, patients received 80 mg of paclitaxel intravenously on days 1, 8 and 15, in 28-day cycles. This was reduced to 60 mg, and in the second 28-day cycle, the alisertib doses were withheld on days 1 through 3 to determine how the paclitaxel worked alone compared with the addition of alisertib. Throughout phase 1, patients received a median of six treatment cycles.

In phase 1, the recommended dosage of alisertib was 40 mg plus 60 mg/m2 of paclitaxel weekly. Phase 2, which ran from March 2012 through August 2013, included 142 patients with recurrent ovarian cancer who were randomized to two groups: one that received the recommended phase 1 regimen and another that received weekly paclitaxel alone. Patients in the alisertib plus paclitaxel arm received a median of 6 cycles, while the paclitaxel-alone arm received 5 cycles.

All 49 patients involved in phase 1 experienced a drug-related side effect, including 38 (78 percent) with grade 3 or 4 side effects. The most common side effects were neutropenia (59 percent) and leukopenia (35 percent), as well as anemia, febrile neutropenia and stomatitis. Serious side effects occurred in nine patients (18 percent), most frequently with febrile neutropenia (12 percent). This led to eleven patients (22 percent) requiring a dose reduction of alisertib and ten patients (20 percent) requiring a dose reduction of paclitaxel. Two patients dropped out of the study as a result of the side effects they experienced in phase 1.

In phase 2, all 73 patients in the alisertib plus paclitaxel arm experienced side effects compared to 66 patients (96 percent) in the paclitaxel-alone arm. In the arm that received both drugs, grade 3 or 4 side effects occurred in 67 patients (92 percent), leading to dose reductions in 54 patients (74 percent) and drug discontinuation in 12 patients (16 percent). Of those who received paclitaxel alone, 35 patients (51 percent) experienced grade 3 or 4 side effects. Side effect-related dose reductions occurred in 17 patients (25 percent) and four patients (6 percent) discontinued the study drug.

While one patient in each arm died during the study, neither death was considered related to the drugs being studied.

Overall, researchers noted an increase in progression-free survival of two months between the two arms: 6.7 months in the patients that received alisertib plus paclitaxel versus 4.7 months in patients who took paclitaxel alone.

Given that the combination shows promising results – and that its safety profile has been found to be generally manageable in patients with recurrent ovarian cancer – the researchers concluded that future studies of alisertib in combination with paclitaxel and other taxanes are warranted.