Liposomal annamycin in combination with high-dose cytarabine (HiDAC) elicited numerically higher complete remission (CR) rates than placebo plus HiDAC in patients with relapsed/refractory acute myeloid leukemia (AML), although these differences did not reach statistical significance, according to data from the first prespecified interim analysis of the pivotal phase 2/3 MIRACLE trial (NCT06788756).1,2
In the first 45 patients enrolled in Part A and analyzed on a full intent-to-treat basis with no patient exclusions, CR after a single treatment cycle reached 43% with annamycin dosed at 190 mg/m² plus HiDAC and 36% with annamycin at 230 mg/m² plus HiDAC, compared with 12% for HiDAC alone.1 Composite CR (CRc) rates were 50% and 57% in the respective annamycin arms vs 29% for the control arm.
The interim review was conducted by the trial's independent data monitoring committee (iDMC), which unanimously concluded that although the primary efficacy end point, the CR rate, did not reach statistical significance, a strong numeric trend favored both experimental arms over the control arm, supporting continuation of the trial. Given the outcomes observed with both dose levels of annamycin, evaluation of both experimental arms will continue.
"These interim phase 2/3 results on such a challenging…population represent a defining moment for Moleculin and, we believe, the strongest clinical validation of Annamycin we have seen to date," Walter Klemp, chairman and CEO of Moleculin, stated in a news release.1 "To see both annamycin dose arms meaningfully outperform the control arm across both the primary end point of CR, as well as CRc, in patients with relapsed/refractory AML is an exceptional outcome. Importantly, these responses were achieved after only a single treatment cycle, providing what we believe is compelling evidence of annamycin's antileukemic activity. We believe these results further validate annamycin's differentiated profile and strengthen our confidence as we advance the MIRACLE trial toward completion."
MIRACLE is a pivotal phase 2/3, multicenter, randomized, double-blind, placebo-controlled, adaptive-design study evaluating liposomal annamycin for injection plus HiDAC vs placebo plus HiDAC as second-line induction therapy in patients aged 18 to 80 years with relapsed/refractory AML per 2022 International Consensus Classification criteria after only 1 prior line of therapy.1,2 An ECOG performance status of 0 to 2 is also required.2 Patients with acute promyelocytic leukemia, prior cumulative anthracycline exposure exceeding 300 mg/m², or FLT3-mutated disease in regions where gilteritinib (Xospata) is available are excluded.2
The trial is divided into Part A, which is designed to identify the optimal annamycin dose, and Part B, which expands enrollment at the selected dose.2
Part A is enrolling 75 to 90 patients who are initially randomly assigned 1:1:1 to receive annamycin at 190 mg/m²/day plus HiDAC, annamycin at 230 mg/m²/day plus HiDAC, or placebo plus HiDAC. Annamycin or a placebo is administered for 3 consecutive days per cycle, and HiDAC is given for 5 consecutive days.
The primary end point of Part A is to identify the optimal annamycin dose for part B, based on CR rate following 1 cycle. CR rate following 1 cycle is the primary end point in Part B. Overall survival is a key secondary end point in both portions of the trial.
Following selection of the optimal dose, approximately 222 additional patients are planned for enrollment in Part B under a 1:1 randomization.
Moleculin reported that 67 of the estimated 90 total patients in Part A have been enrolled, representing approximately 74% of the planned enrollment, as the company advances toward optimal dose selection.1 Efficacy data from Part A are expected to be carried forward into the pivotal analysis once the selected dose arm advances into Part B.1
"From a clinical perspective, these interim results are highly encouraging," Klemp said. "Historically, achieving meaningful remission rates in relapsed/refractory AML has been exceptionally difficult, especially [in patients] pretreated with venetoclax [Venclexta], which is why seeing both annamycin treatment arms outperform the control arm across both efficacy end points is so noteworthy. The remission rates observed to date are particularly compelling when viewed in the context of outcomes historically reported for currently available therapies in this setting, especially given that patients in MIRACLE were evaluated after only a single treatment cycle. While cross-trial comparisons should be made with caution, these findings suggest the potential for a level of clinical activity that could meaningfully advance the treatment landscape for patients with relapsed/refractory AML. If these results continue to be observed as the trial progresses, annamycin could represent an important new option for patients facing a disease with substantial unmet medical need."
