Delivering drugs in combination requires a certain balance, a balance that ensures the drugs act synergistically. And researchers say they have struck the right balance with a new drug that combines two old standbys.
Daunorubicin and cytarabine (or ara-C) have proven activity against acute leukemia. However, neither of the drugs has elicited impressive survival rates when given alone, according to Eric Feldman, MD, of Weill Cornell Medical College.
In a presentation at Chemotherapy Foundation Symposium XXVII, Dr Feldman discussed a new agent comprised of the two drugs that he theorizes will prove more effective than either drug alone.
“When you combine different combinations of cytarabine and daunorubicin, there are some ratios that, in fact, may be antagonistic or just additive,” Dr Feldman said. “But… there are some—particularly this 5-to-1 ara-C-to-daunorubicin—that may be synergistic. And the question is, how do you deliver to the leukemia cell this synergistic combination of drugs?”
For a long time, Dr Feldman said, scientists did not have the appropriate technology to accomplish that. But now they do, and they have made significant strides with the compound CPX-351.
“Basically, this is a liposomal combination of daunorubicin and ara-C,” Dr Feldman said. “But the unique feature is that it fixes a 5-to-1 molar ratio of ara-C with daunorubicin and delivers to the cell this ratio in this concentration.”
To test the tolerability and efficacy of this compound, researchers began a phase 1 trial of CPX-351. The majority of patients on the trial had acute myeloid leukemia, though there were a few with acute lymphocytic leukemia and myelodysplastic syndrome. All were refractory to prior therapy, and most were over the age of 60 years.
The FDA mandated that the initial dose of CPX-351 be very low, so the researchers started with 3 units/m². One unit of CPX-351 is equal to 1 mg of cytarabine and 0.44 mg of daunorubicin. The researchers increased the dose gradually and monitored patients for responses and toxicities.
“We started low… and did not see responses at all until we got to 32 units,” Dr Feldman said. “By 101 [units], we saw multiple responses, and this is the dose that was considered the maximum-tolerated dose.”
This is because, at 134 units, the team observed 3 dose-limiting toxicities. They saw left ventricular systolic dysfunction and 1 patient with hypertensive crisis, although it was not clear whether this event was actually related to the drug.
“The main problem that we found was persistent cytopenias,” Dr Feldman said. “There was 1 patient in this cohort that took over 80 days to achieve a complete remission, meaning recovery of their platelets to 100,000 and neutrophils to 1000. We considered that the true dose-limiting toxicity.”
Apart from this myelosuppression, CPX-351 was well tolerated. Some patients did experience mucositosis, vomiting, and a skin rash, but the rash responded to corticosteroids. Importantly, patients did not experience alopecia.
With these promising results, researchers began a phase 2 study of CPX-351. They enrolled newly diagnosed leukemia patients between 60 and 75 years of age. Patients had high- or intermediate-risk disease.
They were randomized in a 2-to-1 fashion to receive either 100 units of CPX-351 or standard 3 + 7 therapy. The preliminary data from this study were presented at the ASH Annual Meeting in December.
