Amonafide Plus Cytarabine Fails To Meet Primary Endpoint

Amonafide+Cytarabine may not be effective for secondary acute myeloid leukemia, according to ACCEDE trial data

Secondary acute myeloid leukemia (sAML) usually develops within 10 years of treatment for a first cancer, has a poorer prognosis, and is strongly associated with multidrug resistance. Standard treatment involves intensive chemotherapy with cytotoxic agents such as the anthracycline daunorubicin in combination with cytarabine.

The ACCEDE trial compared this sAML treatment with a novel DNA intercalator and topoisomerase II inhibitor that induces apoptosis by disrupting chromatin organization independently of ATP, Amonafide L-malate (AS1413) from London-based Antisoma. The compound has also demonstrated that it is able to evade P-glycoprotein and related transporters that contribute to multidrug resistance.

“There was hope that Amonafide, in combination with a standard protocol of cytarabine, might be better than the usual combination of drugs used to treat sAML patients, which is daunorubicin plus cytarabine,” said Richard M. Stone, MD, clinical director of the adult leukemia program at the Dana-Farber Cancer Institute in Boston.

Stone and colleagues unveiled a poster presentation of their ACCEDE findings at the American Society of Clinical Oncology conference on Friday. In the phase III, multicenter, open-label study, patients aged ≥ 18 years with newly diagnosed sAML were randomized to cytarabine 200 mg/m2 continuous IV infusion daily on days 1—7 plus either AS1413 600 mg/m2 IV over 4 hours daily on days 1–5 (Arm A) or daunorubicin 45 mg/m2 IV over 30 minutes daily on days 1–3 (Arm B), according to the researchers.

“The primary endpoint of the trial was to determine if the complete remission [CR] rate, or the likelihood of a major response, was higher in the group that got the investigative combination drug compared with the group that got the standard treatment combination,” he said in an interview with

The planned sample size of 420 patients provided 89% power to detect a 15% difference at the P=0.05 level (two-tailed) between anticipated CR rates, they noted. The researchers reported that 564 sAML patients were screened and 433 were randomized; 216 to arm A and 217 to arm B. In addition, disease etiology, cytogenetics, and age were balanced among both arms.

“Sadly, there was no improvement in the CR rate of the patients who were randomized to Arm A, compared with those who were randomized to Arm B,” Stone observed. “Actually, the newer regimen did as well as expected, but the older regimen did better than expected.”

The researchers wrote that CR + CR with incomplete blood count recovery was 94/216 (43.5%) in Arm A and 94/217 in Arm B (43.3%) with a P value of 0.966. Also, 30-day mortality was 20.4% in arm A and 12.4% in arm B. Serious adverse events were balanced between the two arms, they noted, and no event occurred in more than 6% of patients in either arm.

Although conventional sAML treatment performed better than expected in the ACCEDE trial, it is still not very good, according to Stone.

“We still need better therapies for patients with this type of intrinsically resistant AML,” he stated.

Stone RM, Allen SL, and Pigneux, et al. A phase III, open-label, randomized comparison of AS1413 (amonafide L-malate) plus cytarabine with daunorubicin plus cytarabine in secondary acute myeloid leukemia (ACCEDE). J Clin Oncol29: 2011 (suppl; abstr 6520).