The first patient has been dosed in a Phase 2 clinical trial examining Tolero Pharmaceuticals‘ investigational CDK9 inhibitor alvocidib as treatment for people with acute myeloid leukemia (AML) who failed prior induction therapy.
The Zella 202 study (NCT03969420) will enroll approximately 128 patients who received induction therapy with Venclexta (venetoclax) plus a hypomethylating agent (HMA) — azacitidine or decitabine — and either failed to achieve a durable (90 days or longer) complete response or whose disease returned after a durable complete response.
Participants are currently being recruited at two sites, in Florida and North Carolina.
The trial will have two parts. The first part will place patients randomly into two groups: one receiving alvocidib with a low dose of the chemotherapy agent cytarabine, and the other given alvocidib alone. Data collected in Zella 202’s first part will determine the appropriate regimen for part two.
The primary goal of the study is to measure the rate of complete remission — with and without complete recovery of blood cells — in both groups. Secondary measures include establishing the optimal treatment regimen for part two, overall survival, rate of complete remission, and duration of complete remission.
The researchers also will assess the treatment’s safety and tolerability, as well as event-free survival — time to treatment failure, relapse, or death, whichever occurs first — as secondary measures.
“The initiation of this study marks an important step toward understanding the potential of alvocidib as a monotherapy or in combination with low-dose cytarabine for these patients,” David J. Bearss, PhD, Tolero’s CEO, said in a press release.
“We believe that patients whose cancers have progressed following treatment with venetoclax may be sensitive to alvocidib and this trial will help us to better understand this hypothesis,” Bearss said.
Alvocidib is a small molecule designed to block a protein called CDK9, responsible for the production of another protein called MCL-1. MCL-1 is essential for the survival of multiple cell types, including lymphocytes and blood stem cells. However, it also prevents cell death in leukemic cells.
By blocking CDK9, alvocidib is expected to reduce MCL-1 levels rapidly, restoring normal cell death pathways in leukemia cells, according to the researchers.
MCL-1 is part of a family of proteins that also includes the BCL-2 protein, which also blocks cell death. Venclexta acts by blocking BCL-2 directly, with the same goal of removing the blockade on cell death.
By studying patients who did not respond to Venclexta, the Zella 202 trial aims to provide them with an alternative method for accomplishing the same biological goal of increasing AML cell death.
“Patients with AML who are resistant to or progressed following treatment with the BCL-2 inhibitor venetoclax in combination with an HMA have limited treatment options, and it has been well established in the literature that a key potential mechanism of resistance to BCL-2 targeted therapy is the switch to a dependence on MCL-1,” Bearss said.
In addition to Zella 202, alvocidib is being evaluated in four additional trials. One such trial is a randomized Phase 2 study (NCT02520011) called Zella 201 involving 79 participants. It is testing whether adding alvocidib to a combination of the chemotherapy agents cytarabine and mitoxantrone improves the outcomes of patients with a form of relapsed or refractory AML that is dependent on the protein MCL-1.