FDA Lifts Partial Clinical Hold on TakeAim Lymphoma Study of Emavusertib/Ibrutinib

The FDA has lifted the partial clinical hold on the phase 1/2 TakeAim Lymphoma clinical trial of emavusertib (CA-4948). The decision comes after the FDA reviewed comprehensive data supporting emavusertib, according to an announcement by Curis, Inc.¹

The partial clinical hold was placed on the TakeAim Lymphoma study on April 11, 2022, by the FDA Division of Hematologic Malignancies 2, a division that regulates clinical studies in lymphoma. At the same time, the FDA’s Division of Hematologic Malignancies 1 placed a partial clinical hold on the TakeAim Leukemia study.

To be able to continue the TakeAim Lymphoma study, Curis, Inc agreed to develop a strategy to identify and manage patients with rhabdomyolysis and enroll at least 9 patients to receive a 200-mg dose of emavusertib combined with ibrutinib (Imbruvica).

"We are excited to announce that FDA has completed its review of the TakeAim Lymphoma study and has lifted the partial clinical hold. We are working with our clinical sites to quickly resume enrollment of new patients in this study in the third quarter," James Dentzer, president and chief executive officer of Curis, said in a press release.

TakeAim Lymphoma is a multicenter, open-label, dose-escalation and dose-expansion trial. Across 3 treatment arms, emavusertib will be evaluated as a single agent at multiple dose levels, and in combination with ibrutinib at 560 mg once daily. Approximately 181 patients with lymphoma will be enrolled and analyzed in 1 of 4 phases that will be carried out. Part A will assess escalating doses of emavusertib in patients with non-Hodgkin lymphoma (NHL), Waldenstrom macroglobulinemia (WM), lymphoplasmacytic lymphoma (LPL), chronic lymphocytic leukemia, and small lymphocytic lymphoma (CLL/SLL). In part A2, escalating doses of the experimental agent in combination with ibrutinib will be evaluated in the same disease groups observed in part A1.²

Part B of the study is the dose-expansion phase during which emavusertib/ibrutinib will be evaluated in 4 disease-specific cohorts. The first 3 disease-specific cohorts explored in part B include marginal zone lymphoma (MZL; cohort 1), activated B-cell diffuse large B-cell lymphoma or extranodal subtypes (cohort 2), and primary central nervous system (CNS) lymphoma (cohort 3). In cohort 4, ibrutinib monotherapy will be administered to patients who developed adaptive, secondary resistance. The diseases included in cohort 4 are mantle cell lymphoma, MZL, CLL/SLL, or WM/LPL.

Primary end points to be explored in part A of the TakeAim Lymphoma study include safety/tolerability determined by dose-limiting toxicities, the maximum-tolerated dose of emavusertib monotherapy, and emavusertib in combination with ibrutinib, and the recommended phase 2 dose of emavusertib alone and combined with ibrutinib. The part B primary end points include complete response rate and overall response rate (ORR) of the combination.

Secondary end points to be assessed in the study include pharmacokinetics, ORR, duration of response, and disease control rate. In part B only, the study will estimate the blood-brain barrier penetration in patients with CNS lymphoma.

Those eligible for the study are male and female patients aged 18 years or older with a life expectancy of at least 3 months and an ECOG performance status of 0 or 1. The study excluded individuals with active CNS involvement other than CNS lymphoma, who had radiotherapy delivered to non-target lesions involving more than 25% of the bone marrow within 1 week of the study, and prior anti-cancer treatment within 14 days. Patients actively receiving or who plan to receive certain glucocorticoid therapies, used an investigational agent within 21 days of starting the study, have acute or chronic toxicity caused by anti-cancer therapy, have allergy or hypersensitivity to the study drugs, or have certain subtypes of B-cell NHL were also excluded.

Based on the partial clinical hold period, preliminary data from the TakeAim Lymphoma study will now be available in 2023. Further, Curis, Inc and the FDA Division of Hematologic Malignancies 2 have ongoing discussions about the recommended dose and development path for emavusertib.¹

_REFERENCE:

_{1. FDA lifts partial clinical hold on the TakeAim Lymphoma study of emavusertib. Curis, Inc. News release. August 18, 2022. Accessed August 19, 2022. https://prn.to/3A6N2Yf}

_{2. A study of CA-4948 in patients with relapsed or refractory hematologic malignancies. Clinicaltirals.gov. Updated April 7, 2022. Accessed August 19, 2022. https://bit.ly/3Axg9W8}