Liposomal Drug Delivery Platform Yields Significant Improvements Over 7+3 Drug Delivery in Phase III Trial of Secondary AML

Liposomal Drug Delivery Platform Yields Significant Improvements Over 7+3 Drug Delivery in Phase III Trial of Secondary AML

Dr. Jeffrey E. Lancet
A phase III trial of the novel complex of CPX-351and a nanoscale drug delivery complex met its primary endpoint of improved overall survival (OS) compared with “7+3” delivery (cytarabine given for 7 consecutive days and daunorubicin given on days 1, 3, and 5) among older patients with newly diagnosed high-risk secondary acute myeloid leukemia (AML; Abstract 7000).

CPX-351 is a formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio within 100-nm diameter bilamellar liposomes. The specific ratio for inclusion was determined in laboratory testing that showed a molar ratio of 5:1 maximized synergy and minimized antagonism. Selective uptake of the encapsulated formulation by leukemic cells was confirmed in animal leukemia models.

Several mechanisms for why the combination may confer greater pharmacokinetic potential have been proposed, explained Jeffrey E. Lancet, MD, of H. Lee Moffitt Cancer Center & Research Institute. Dr. Lancet presented the study results during the “Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant” Oral Abstract Session on June 4. The liposomal encapsulation may be beneficial for effecting drug penetration, he said, or the molar ratio may facilitate better complementary drug activity.

“We think, biologically, the ability to deliver the drugs in a synergistic ratio that is maintained provides an advantage over free drug,” Dr. Lancet said.

Study Results

In the study, 309 patients at 39 U.S. and Canadian sites were randomly assigned to receive one to two induction cycles of CPX-351 or 7+3 followed by one to two cycles of consolidation therapy. The treatment groups were well balanced for sex, race, age, performance status, AML subtype, myelodysplastic syndromes (MDS)-related cytogenetics, and exposure to prior therapy with hypomethylating agents, Dr. Lancet said.

OS was significantly improved with CPX-351, with a median OS of 9.56 months in the CPX-351 arm compared with 5.95 months in the 7+3 arm (hazard ratio [HR]  0.69; p = 0.005). There were also favorable benefits for the study drug compared to 7+3 for other efficacy endpoints, including event-free survival and response rate.

The 60-day mortality rate was more favorable in the group receiving CPX-351 compared with the group treated with the 7+3 regimen (13.7% vs. 21.2%). Of the deaths that occurred within 60 days, 10.5% in the CPX-351 group were due to adverse events, with 3.3% attributable to progressive AML; in the 7+3 group, 9.9% of deaths were due to adverse events and 11.3% were attributable to progressive AML.

Hematopoietic transplant was performed in 34% and 25% of patients in the CPX-351 and 7+3 arms, respectively.  However, those patients in the CPX-351 arm who underwent transplant appeared to have more favorable outcomes, Dr. Lancet said. At the time of transplant, median OS in the CPX-351 arm had not yet been reached, and was 10.25 months in the 7+3 arm (HR 0.46; p = 0.0046). Grade 3 to 5 adverse events were similar in frequency and severity in both arms, he said.

Discussion

The findings from the trial clearly demonstrated a benefit for the liposomal, encapsulated drug delivery platform, even if the exact mechanism explaining superior outcomes is not abundantly clear, Richard A. Larson, MD, of the University of Chicago, said during his discussion of the study results.

Dr. Richard A. Larson
“Three days of the CPX-351 provided significantly better survival than the 7+3 regimen, with an improvement of median survival of 3.5 months. In the experimental arm, fewer patients were refractory to the induction therapy, there was a lower early mortality, and, as result, more patients [underwent] transplant. The bottom line is that more patients were alive at 24 months,” Dr. Larson said.

After 24 months of follow-up, 31.1% of patients in the CPX-351 treatment group were still alive compared with 12.3% in the 7+3 group.

Dr. Larson proposed several hypotheses for why results were improved in the CPX-351 arm, each of which could have important implications:

  • If the 5:1 molar ratio is the reason, then “we need to learn more about the chemistry of combining these two agents”;
  • If it is the liposomal delivery, then “this could be extrapolated to other combinations of chemotherapy drugs”;
  • If it was because fewer patients died during induction, then “it might suggest that at least within this group of patients, we may be treating too aggressively with 7+3 regimens”; or
  • If it was because more patients underwent transplant, “that seems to be the bottom line here,” he said.

“I do think these data will be sufficient for U.S. Food and Drug Administration approval, and after approval, this agent should be considered for frontline use in this subset of patients with AML,” Dr. Larson said.

—Bryan Bechtel