Alvocidib Trial Launches in MDS

The first patient has been diagnosed with alvocidib, administered in sequence following azacitidine, in the expansion of the phase 1b/2 Zella 102 study in patients with myelodysplastic syndromes (MDS), according to Tolero Pharmaceuticals, Inc., the company developing the CDK9 inhibitor.¹

The study (NCT03593915) is accruing patients with either previously treated MDS or those who have been treated with ≤6 cycles with hypomethylating agents. Patients on the open-label, dose-escalation study receive alvocidib administered in sequence after either decitabine or azacitidine.

The primary objective of the phase 1b part of the study is to determine the maximum-tolerated dose and recommended phase 2 dose of alvocidib, and the phase 2 part will have a primary end point of objective response rate with alvocidib when administered after a hypomethylating agent.

"We are pleased that this study now includes both standard of care hypomethylating agents for patients with myelodysplastic syndromes. In addition, the expansion of this study offers an alternative alvocidib dosing schedule, which reduces the amount of time patients spend in infusion," David J. Bearss, PhD, chief executive officer, Tolero, stated in a press release.

"Preclinical research suggests that treatment with hypomethylating agents may sensitize MDS blast cells to suppression of MCL-1 through alvocidib. We look forward to building our understanding of the potential role of alvocidib in this patient population," added Bearss.

Overall, the Zella 102 trial aims to enroll 49 patients and the estimated primary completion date is February 2023.² Patients must be aged ≥18 years, have an ECOG performance status of ≤2 at baseline, and have a life expectancy of at least 3 months. Enrollment is prohibited if patients have concomitant severe cardiovascular disease, or a concomitant tumor requiring chemotherapy or any tumor that required chemotherapy fewer than 6 months prior to study enrollment.

Data with alvocidib in patients with acute myeloid leukemia (AML) from the phase 1 Zella 101 study were presented at the 2019 European Hematology Association Congress.³ The preliminary data from the study included 18 evaluable patients with newly diagnosed AML. Patients received alvocidib in combination with cytarabine and daunorubicin.

Of the 18 evaluable patients, 14 (78%) reached a complete remission (CR) or CR with incomplete hematologic recovery (CRi). Eleven of these 14 patients reached the 30-day post-study evaluation as outlined in the study protocol, and 3 of these patients went on to receive stem cell transplant. Further, 6 (67%) of 9 patients with poor cytogenic risk achieve a CR/CRi. Overall, at the time of the analysis, which occurred at a median follow-up of 70 days, 21 of 22 patients enrolled on the study were alive.

There were no new safety signals in the study compared with prior studies of alvocidib. The most common adverse events across all grades were diarrhea, tumor lysis syndrome, infections, and elevated AST levels.

Several other trial are exploring alvocidib, including the phase 2 Zella 202 trial (NCT03969420) in patients with AML who are relapsed/refractory to combination therapy with venetoclax plus decitabine or azacitidine, and the phase 2 Zella 201 study (NCT02520011) of alvocidib in combination with cytarabine and mitoxantrone in patients with relapsed/refractory MCL-1–dependent AML.

References

1. Tolero Pharmaceuticals Announces Expansion of the Zella 102 Study in Patients with Intermediate and High-Risk Myelodysplastic Syndromes (MDS). Published May 14, 2020. https://www.toleropharma.com/our-news/press-releases/press05142020. Accessed May 14, 2020.
2. A Phase 1b/2 Study of Alvocidib Plus Decitabine or Azacitidine in Patients With MDS. NIH ClinicalTrials.gov.Last updated May 5, 2020. https://clinicaltrials.gov/ct2/show/NCT03593915. Accessed May 14, 2020.
3. Tolero Pharmaceuticals Presents Clinical Data from Ongoing Phase 1 Zella 101 Study Evaluating Investigational Agent Alvocidib in Combination with Cytarabine and Daunorubicin in Patients with Newly Diagnosed AML at EHA 2019. Published June 14, 2019. https://www.toleropharma.com/our-news/press-releases/press06142019. Accessed May 14, 2020.