CX-01 with standard induction chemotherapy shows promise among elderly patients with AML

Issue: July 25, 2019

CHICAGO — The low anticoagulant heparin derivative CX-01 combined with standard induction therapy induced encouraging rates of complete response and EFS among elderly, fit patients newly diagnosed with acute myeloid leukemia, according to results of a randomized phase 2 trial presented at ASCO Annual Meeting.

Perspective from James McCloskey , MD

“CX-01 is well-tolerated when combined with conventional chemotherapy for the treatment of AML in elderly fit patients,” Tibor Kovacsovics, MD, medical director for inpatient services in the division of hematology and hematologic malignancies and associate director of hematologic malignancy clinical research at The University of Utah, said during the presentation. “Adverse events are consistent with what is expected for aggressive AML therapy.”

A previous study by Kovacsovics and colleagues showed that adding CX-01 (Cantex Pharmaceuticals) to standard 7 + 3 cytarabine and idarubicin induction led to a complete remission rate of 92% among a small cohort of 12 patients with AML.

In the current randomized, dose-finding study, Kovacsovics and colleagues evaluated the same drug combination among newly diagnosed elderly patients with AML.

Researchers randomly assigned 75 (median age, 68 years; range, 60-79; 40% women) physically fit patients older than age 59 years to one of the following regimens:

induction with idarubicin and cytarabine on a 7 + 3 schedule only (control group; n = 26);
7 + 3 with a lower dose (0.125 mg/kg/hour) of CX-01 (low-dose group; n = 25); or
7 + 3 with a higher dose (0.25 mg/kg/hour) of CX-01 (high-dose group; n = 24).

Baseline characteristics were similar across groups. Ten patients were not evaluable due to withdrawal, including six from the high-dose group, three from the low-dose group, and one from the control group.

“We unfortunately had a high risk of dropouts, which happened mostly in the high-dose group,” Kovacsovics said. “As a consequence, we had difficulty analyzing out primary endpoint of response rate. It is for that reason we decided to evaluate the patients on the evaluable basis as opposed to the intent-to-treat basis.”

Patients who achieved complete response (CR) received consolidation therapy that included up to three cycles of intermediate-dose cytarabine (1,000 mg/m² every 12 hours on days 1, 3 and 5) with or without the same dose of CX-01 for all three groups.

Researchers administered CX-01 as a continuous infusion after a 4 mg/kg bolus until chemotherapy completion.

A composite CR rate — CR plus CR with incomplete blood count recovery — and safety served as the study’s primary endpoints. Secondary endpoints included EFS and OS.

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Results for 65 patients evaluable for response — not on an intent-to-treat basis — showed the highest composite CR rate among patients who received the higher dose of CX-01 (high-dose group), with 89% of these patients achieving a composite CR vs. 58% of patients in the control group and 50% of patients in the low-dose group (P = .03).

The high-dose group also demonstrated significant improvement in median EFS (23.4 months) compared with the control group (9 months) and the low-dose group (6.5 months; P = .011). Median OS was not reached in the high-dose group and was 12 months in the low-dose group and 11.2 months in the control group (P = .042).

These data showed the low-dose and control groups had similar EFS and OS.

CX-01 appeared well-tolerated and did not increase the incidence of bleeding in the low- and high-dose groups.

The most common severe adverse events included febrile neutropenia (7 total cases; 3 in each CX-01 group and 1 in the control group) and respiratory failure (3 total cases; 2 in CX-01 groups and 1 in the control group).

The high drop out rate served as the study’s primary limitation.

“These results suggest that CX-01 given in combination with standard induction may improve outcomes in patients fit for induction and candidates for curative therapy, irrespective of their molecular profile,” Kovacsovics said. – by John DeRosier

Reference:

Kovacsovics T, et al. Abstract 7001. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosure s : Kovacsovics reports consultant/advisory roles with Celgene and Novartis and research funding from AbbVie, Novartis and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.

Perspective

James McCloskey , MD

This is still an early randomized clinical trial. It builds on data that were published in 2018 that showed very impressive response rates when CX-01 was combined with standard induction therapy. The results here are not necessarily surprising, but we didn’t know whether there would be unexpected toxicities at these doses.

The toxicities seem to be consistent with the earlier phase 1 and phase 2 clinical trials where we did not see a lot of increased complications including bleeding risks. This isn’t surprising because, while CX-01 is a heparin derivative, we’ve never seen that it has real anticoagulant activity.

If it’s true that there are not significant increased toxicities with this agent, then that’s certainly appealing because we have struggled with adding agents to intensive chemotherapy, especially in older patients. Any gain in efficacy is often blunted by increase toxicity.

The CR rates in this trial in the higher-dose cohort are extremely promising and more than what we were anticipating. That being said, the trial is still accruing, and we need more time to see where this plays out. Also, there was a high withdraw rate, which isn’t surprising, but it does impact our ability to interpret the data.

In terms of an FDA approval, it’s sometimes hard to know what information the FDA is looking for to approve a new therapy. Ideally, we would have matured randomized data that shows a significant survival benefit to alter the upfront management of patients with AML.

The most important finding from this abstract is the lack of toxicity and remarkable response rates. It will be interesting to see where the OS figures play out and how long the duration of response is for this drug.

James McCloskey , MD

Hackensack University Medical Center

Disclosures: McCloskey reports no relevant financial disclosures.