The FDA has placed a partial clinical hold on a phase I trial assessing the autologous T-cell therapy ACTR707 in combination with rituximab for patients with CD20-positive, B-cell non-Hodgkin lymphoma due to a safety concern.
The FDA has placed a partial clinical hold on a phase I trial (ATTCK-20-03; NCT03189836) assessing the autologous T-cell therapy ACTR707 in combination with rituximab (Rituxan) for patients with CD20-positive, B-cell non-Hodgkin lymphoma due to a safety concern.1
The hold was issued after the company reported that 1 patient enrolled on the trial experienced a grade 3 serious adverse event (AE) of a potential new malignancy that could have been related to treatment with ACTR707. Patients who previously received the autologous T-cell therapy can still receive treatment with rituximab.
In a report, it is noted that Unum Therapeutics, the developer of ACTR707, will work closely with the study site, as well as the FDA, to further review this AE.
The partial hold follows the company’s announcement that it had planned to conclude its clinical program for ACTR707, since it had planned to undergo restructuring and turn its focus to preclinical asset for solid tumor development.
In the phase I trial, investigators evaluated the combination of ACTR707 with rituximab in patients with relapsed/refractory CD20-positive B-cell non-Hodgkin lymphoma. To be eligible for enrollment, patients must have had histologically confirmed relapsed/refractory CD20-positive B-cell lymphoma with disease progression or recurrence following prior therapy, in 1 of the following subtypes: diffuse large B-cell lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, and TH-follicular lymphoma.
Patients must have had harbored CD20 expression, ≥1 measurable lesion, must have received prior adequate therapy, had an ECOG performance status of 0 or 1, a life expectancy of ≥6 months, and a platelet count ≥50,000 µL.
Those with active central nervous system (CNS) involvement; had clinically significant cardiac disease, active infection, or CNS disorder; had a clinical history or evidence of autoimmune disease; known bone marrow involvement; or had received prior alemtuzumab, fludarabine, cladribine, clofarabine, external bean radiation, rituximab or another monoclonal antibody, other lymphotoxic chemotherapy, or experimental agents within 3 half-lives prior to enrollment were not eligible for the study.
The primary endpoint is safety as assessed by dose-limiting toxicities, as well as maximum-tolerated dose and the proposed recommended phase II dose. Secondary endpoints include overall response rate, duration of response, progression-free survival, overall survival, and pharmacokinetics.
Nonclinical data that were previously presented supported the ongoing phase I trial. Results showed that when ACTR707 was combined with rituximab, ACTR707 T cells had potent activation, proliferation, cytokine production, and tumor-directed cytotoxicity in the presence of CD20-positive lymphoma cell lines.2 ACTR707 T-cell in vitro activity was dependent on rituximab and was dose-titratable.
Moreover, ACTR707 T cells were found to have potent antitumor activity in vivo in an aggressive Raji lymphoma xenograft model in NSG mice; ACTR707 T-cell antitumor activity was ACTR T-cell and rituximab dose-dependent. Additionally, higher T-cell numbers and antibody concentrations facilitated improved responses.
The combination also outperformed a CD19-targeted CAR T-cell product against aggressive Raji tumors in vivo. Overall, the investigators concluded that these early findings demonstrated the specificity and adaptability of the ACTR707 T-cell therapy as a method to target diverse cancer antigens.
ACTR707 is also being evaluated in combination with trastuzumab (Herceptin) for the treatment of patients with HER2-positive advanced cancers. Enrollment for this trial was complete, as of a January announcement.3