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Sequential Alvocidib Followed by Cytarabine + Mitoxantrone in AML

Simoneaux, Richard

doi: 10.1097/01.COT.0000553153.26180.b5

SAN DIEGO— “Alvocidib is a potent inhibitor of CDK9, a protein that regulates RNA polymerase II activity, thereby driving the transcription of genes involved in cell survival, most notably MCL-1,” explained Joshua Zeidner, MD, Assistant Professor at the UNC Lineberger Comprehensive Cancer Center in Chapel Hill and lead investigator of the Zella 201 study.

“The regimen of alvocidib, followed by cytarabine and mitoxantrone (ACM), has been investigated in serial phase I and II studies in both newly diagnosed and relapsed/refractory acute myeloid leukemia (R/R AML) patients,” Zeidner noted. “Although ACM has demonstrated clinical activity in AML, we were interested in assessing whether patients dependent on MCL-1 for leukemia survival may respond best to ACM.”

To evaluate the potential for the ACM sequential regimen in patients with MCL-1-dependent R/R-AML, the phase II Zella 201 study (NCT02520011) was undertaken by Zeidner and colleagues. “In this study, the MCL-1 dependence of the patients' disease was assessed by an investigational strategy known as NOXA profiling,” Zeidner stated. “In the era of targeted therapy for cancer, this treatment strategy harnesses the intrinsic biologic mechanism for leukemia cell survival beyond genomic profiling.” At the 2018 ASH Annual Meeting, Zeidner presented results from this study (Abstract 30).

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“Zella 201, a multicenter phase II study of ACM in R/R AML patients with MCL-1 dependence, is composed of two stages: Stage I is a single-arm study of ACM in R/R MCL-1-dependent AML patients with the primary objective to assess overall complete remission (CR) (CR + CR with incomplete recovery (CRi)) rates in the first 23 patients,” Zeidner explained. “Stage II is a randomized phase II study of ACM versus CM (cytarabine and mitoxantrone only) in MCL-1-dependent R/R AML patients with a primary objective of assessing CR rates between ACM and CM.”

Among key eligibility criteria were the following: 18-65 years of age; refractory to 1-2 cycles of induction therapy, or in first relapse AML with CR of 2 years or less; 40 percent or greater myeloblast MCL-1 dependency, as determined by BH3 profiling; ECOG PS 0-2; and no major organ dysfunction. Patients receiving prior allogeneic stem cell transplant were considered eligible if it had been more than 2 months post-SCT and they had no active graft-versus-host disease.

When asked about study goals, Zeidner responded, “The primary endpoint was the rate of overall CR in the first 23 patients enrolled, while secondary endpoints included durability of response (i.e., disease-free survival and event-free survival), overall survival, and toxicity assessment.” Stage I was considered to be positive if 13 or more CRs were observed in the first 23 evaluable patients.

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Study Results

ASH 2018 Abstract 30

During screening, a total of 170 R/R AML patients were tested and, of these, 48 (28%) were found to have MCL-1-dependent disease. From these patients, 25 were enrolled in stage I, and ultimately, 23 were deemed evaluable for response. The median MCL-1 dependence score was 53 percent, with a range of 41-98 percent. The overall CR/CRi rate was 57 percent (13/23), which met the primary endpoint for stage I.

The most frequent NCI Common Terminology Criteria for Adverse Events grade 3 or higher treatment-emergent non-hematologic AEs noted in more than one patient in the safety population (n=25) were tumor lysis syndrome (grade 4—8%, grade 3—20%); diarrhea (grade 3—24%); increased AST (grade 4—8%, grade 3—12%), and sepsis (grade 5—16%, grade 4—4%).

“To date, the overall 30- and 60-day mortality rates were 16 percent and 20 percent, respectively, due to sepsis (n=4) and mitral valve rupture (n=1),” Zeidner noted.

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“We have completed stage I of this study. The study was statistically designed to meet its primary endpoint if there were 13 or more CRs in the first 23 evaluable patients. In our results for stage I, we found that there were 13/23 CRs, thus meeting the primary endpoint,” Zeidner said.

“I think the main lesson from this study is that MCL-1 dependence can be determined fairly rapidly (within 48 hours) in order to serve as a biomarker of response to alvocidib. Our encouraging findings from stage I of this study suggest that MCL-1 dependence may predict for response to alvocidib.”

Regarding the timing of the dosing regimen, Zeidner noted, “ACM was designed as a timed sequential regimen due, in part, to alvocidib's inhibition of CDK4/6, in addition to CDK9; CDK4/6 regulate the progression through G1-S phase in the cell cycle, while initial pre-clinical studies suggested that alvocidib's primary mechanism of action was inhibition of CDK4/6.

“Cytarabine and mitoxantrone, S-phase-dependent cytotoxic agents, are administered 72 hours after alvocidib dosing to effectively prime cytotoxicity against residual leukemic cells entering cell cycle. However, more recent data suggests that the demonstrable tumor lysis and anti-leukemic activity of alvocidib is predominantly driven by its CDK9 inhibition,” Zeidner added.

In summary, “Our findings from stage I of Zella 201 demonstrated a ‘proof-of concept’ that we can utilize an MCL-1 biomarker score to determine MCL-1 dependence and eligibility of a multicenter phase II study. Moreover, our findings revealed clinical activity for the ACM regimen in R/R MCL-1-dependent AML with an overall CR/CRi rate of 57 percent in stage I. In stage II of this study, which is actively recruiting, we plan to enroll 106 patients to determine whether ACM significantly improves the CR rate compared with cytarabine and mitoxantrone alone,” Zeidner noted. “We are also investigating the efficacy of the addition of alvocidib to other therapeutic agents in AML and myelodysplastic syndromes.”

When queried as to whether this strategy may have potential for other MCL-1-driven malignancies, Zeidner replied, “Yes, the NOXA profiling biomarker score can potentially be used to determine MCL-1 dependence in other tumors, potentially as a tumor-agnostic strategy, and thereby assess the therapeutic activity of alvocidib in this setting.”

Richard Simoneaux is a contributing writer.

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