Solid Tumor Cell Therapy Combination Trial Cleared to Continue

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There were no deaths or safety signals identified by the DSMB for the 3 treated patients in cohort 1.

The Israeli Ministry of Health (IMOH) has cleared a phase 1/2 clinical trial (NCT05581719) investigating Enlivex’s Allocetra cell therapy for the treatment of solid tumors for continuation, following a positive review from an independent data and safety monitoring board (DSMB) of data from the first cohort.1

Allocetra is an investigational allogeneic cell therapy intended to reprogram macrophages that have become "pro-tumor" tumor associated macrophages (TAMs) back into a homeostatic state.2 It is comprised of non-HLA matched peripheral blood mononuclear cells derived from a healthy human donor that have been induced into an apoptotic stable state. The clinical trial’s first cohort treated 3 patients with Allocetra as monotherapy.1 Allocetra was administered either intravenously (IV) or intraperitoneally (IP), depending on tumor location, in 3 once-weekly doses. At 21 days of follow-up from the first dose, there were no deaths or safety signals identified by the DSMB for the 3 treated patients. The DSMB recommended that the trial continue without modifications to its design. In light of the data, the IMOH provided regulatory clearance for Enlivex to begin recruiting patients for the trial’s next 2 cohorts, which will treat patients with higher doses of Allocetra. In 1 of these cohorts, patients will receive Allocetra as a monotherapy, while in the other cohort, patients will receive Allocetra in combination with the anti-PD1 immune checkpoint inhibitor nivolumab.

"We are pleased with the safety profile of Allocetra as demonstrated in the first 3 patients in this trial,” Oren Hershkovitz, PhD, chief executive officer, Enlivex, said in a statement regarding the news.1 “We look forward to initiating the next 2 cohorts in which higher doses of Allocetra will be administered in patients, allowing Enlivex to obtain additional safety data as well as a potential indication of effect."

In total, the multicenter, open-label, dose escalation trial is anticipated to enroll approximately 48 patients aged 18 years and older who have advanced, unresectable or metastatic solid tumors. Patients are required to have relapsed or been refractory to available approved therapies, or to be ineligible for or declined treatment with additional standard of care systemic therapy. Patients with peritoneal carcinomatosis may be included if an appropriate IP catheter or port is placeable. Patients are additionally required to have measurable disease, an Eastern Cooperative Oncology Group score of 1 or lower, and adequate renal, hepatic, and bone marrow function. Patients with clinically unstable primary central nervous system (CNS) malignancy or CNS involvement; clinically significant uncontrolled infection; autoimmune or inflammatory diseases requiring systemic immunosuppression; clinically significant cardiovascular disease; severe pulmonary diseases; or additional malignancies will be excluded from participation. Participants in the trial’s second stage, which will treat patients with the combination therapy approach, must additionally not have previously had an immune checkpoint inhibitor (ICI)-related adverse reaction that resulted in discontinuation of the ICI.

The study’s primary end point is safety based on dose-limiting toxicities. Secondary end points include the overall response rate (ORR) and best ORR, clinical benefit rate, duration of response, time to response, progression-free survival, and overall survival. Changes in immune cell and cytokine profiling in the peritoneal fluid will also be evaluated. The trial is recruiting at several centers in Israel and is estimated to be completed in June 2024.

The IMOH originally cleared the trial for initiation in August 2022.2 Allocetra had previously demonstrated potential in preclinical research. In an ovarian cancer mouse model, mice treated with Allocetra in combination with an anti-PD1 checkpoint inhibitor showed an 83% increase in survival duration compared to an untreated group.3 Additionally, the combination therapy group had a survival probability up to 50%, compared to 0% in the untreated group. In addition to solid tumors, Allocetra is also being evaluated for the treatment of patients with peritoneal metastasis (NCT05431907), patients with COVID-19 (NCT04659304, NCT04922957), and patients with sepsis (NCT04612413).

REFERENCES
1. Enlivex announces positive DSMB recommendation and IMOH clearance to continue phase I/II trial of Allocetra in patients with advanced solid tumors. News release. Enlivex Therapeutics Ltd. Janaury 25, 2023. Accessed Janaury 30, 2023. https://finance.yahoo.com/news/enlivex-announces-positive-dsmb-recommendation-133700145.html 
2. Enlivex receives Israeli Ministry of Health approval for the initiation of a phase I/II trial evaluating Allocetra alone and in combination with a PD1 checkpoint inhibitor in patients with advanced solid tumors. News release. Enlivex Therapeutics Ltd. August 17, 2022. https://www.globenewswire.com/news-release/2022/08/17/2499939/0/en/Enlivex-Receives-Israeli-Ministry-of-Health-Approval-for-the-Initiation-of-a-Phase-I-II-Trial-Evaluating-Allocetra-Alone-and-in-Combination-with-a-PD1-Checkpoint-Inhibitor-in-Patie.html 
3. Enlivex announces new preclinical data in ovarian cancer showing a substantial survival benefit when Allocetra is combined with PD-1 checkpoint inhibition at the American Society of Clinical Oncology (ASCO) annual meeting. News release. Enlivex Therapeutics Ltd. May 31, 2022. https://www.globenewswire.com/en/news-release/2022/05/31/2453221/0/en/Enlivex-Announces-New-Preclinical-Data-in-Ovarian-Cancer-Showing-a-Substantial-Survival-Benefit-when-Allocetra-is-Combined-with-PD-1-Checkpoint-Inhibition-at-the-American-Society-o.html 
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