The FDA has placed a partial clinical hold on the open-label, dose-escalating phase 1/2 TakeAim Lymphoma study investigating the safety and efficacy of emavusertib in patients with relapsed or refractory B-cell malignancies.
The FDA has placed a partial clinical hold on the open-label, dose-escalating phase 1/2 TakeAim Lymphoma study (NCT03328078) investigating the safety and efficacy of emavusertib (previously CA-4948) in patients with relapsed or refractory B-cell malignancies.1
Earlier this month, the regulatory agency placed a partial clinical hold on the phase 1/2a TakeAim Leukemia trial (NCT04278768), which is examining emavusertib as a monotherapy and in combination with azacitidine or venetoclax (Venclexta) in patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).2
The FDA had requested additional data from the trial, including information on the death of a patient with relapsed or refractory AML who experienced rhabdomyolysis, among other conditions, which has previously been identified to be a dose-limiting toxicity linked with emavusertib. Safety, efficacy, and other data pertaining to this toxicity, and the determination of the recommended phase 2 dose (RP2D) of the agent for the research, were also requested.
With this extension of the partial hold, no new patients can enroll to TakeAim Lymphoma, and those who are currently enrolled and are deriving clinical benefit from the investigative treatment can continue to receive emavusertib at 300 mg twice daily or lower after they reconsent.
“We reiterate our previous comments: we are committed to ensuring the safety of patients in our studies and to working collaboratively with the FDA to develop therapies that meaningfully improve and extend patients’ lives,” James Dentzer, chief executive officer of Curis, Inc., stated in a press release. “Given the clinical profile of emavusertib observed to date, we are hopeful that the study can be resumed soon, after appropriate review. We continue to be confident in the potential of emavusertib to address the high unmet need of patients with B-cell cancers, AML, or MDS.”
The multicenter, open-label trial enrolled those with a diagnosis of histopathologically confirmed B-cell hematologic malignancies who are at least 18 years of age, have an ECOG performance status of 0 or 1, and a life expectancy of at least 3 months.3
Part A of the trial was designed to evaluate escalating doses of emavusertib as a single agent (part A1) or in combination with ibrutinib (Imbruvica) for those with non-Hodgkin lymphoma, Waldenström macroglobulinemia or lymphoplasmacytic lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (part A2).
Once the dose for the combination regimen is identified, part B of the trial will launch; this includes an expansion phase that will allow for the evaluation of efficacy and safety of the RP2D of emavusertib and ibrutinib in the following disease-specific cohorts: marginal zone lymphoma (cohort 1), activated B-cell diffuse large B-cell lymphoma or extranodal subtypes (cohort 2), primary central nervous system (CNS) lymphoma (cohort 3), and those receiving ibrutinib monotherapy who have developed adaptive, secondary resistance (cohort 4).
The primary outcome measures for part A of the trial include safety and tolerability of emavusertib as a single agent and in combination with ibrutinib, maximum-tolerated dose of the agent alone and in combination, and RP2D of the agent alone and in combination. The primary outcome measures for part B include assessment of complete response rate achieved with the combination and overall response rate (ORR) with the combination.
Secondary outcome measures include pharmacokinetic data with emavusertib, as well as ORR, duration of response, disease control rate, progression-free survival, and overall survival with emavusertib alone and in combination with ibrutinib. In part B specifically, investigators seek to estimate the blood-brain barrier penetration with this approach in those with CNS lymphoma.
The biotechnology company shared expectations to provide guidance on the timing of discussing the potential for a rapid registrational path for emavusertib with the FDA once the partial clinical holds are addressed and resolved, and the associated impact on the trials is identified.