The Phase 1/2a trial (NCT04171843) is expected to begin enrolling eligible adults in March at multiple U.S. sites, the company said.
Precision made the announcement after the U.S. Food and Drug Administration (FDA) cleared its investigational new drug (IND) application, a necessary step in a clinical study, and designated PBCAR269A an orphan drug as a potential myeloma treatment.
“FDA acceptance of the IND for PBCAR269A further underscores the ongoing progress in our allogeneic CAR T pipeline,” Matt Kane, chief executive officer of Precision BioSciences, said in a press release.
Traditional CAR T-cell therapy involves harnessing T-cells a patient’s immune system, and genetically engineering them to produce a protein — called chimeric antigen receptor, or CAR — designed to target a specific cancer molecule.
Precision reports that it has improved upon this system by using T-cells collected from healthy donors, allowing for an “off-the-shelf” treatment that could potentially be used in numerous patients. Traditional approaches require that the treatment be tailored to the individual receiving it.
A treatment that utilizes cells from an unrelated donor is allogeneic. One drawback of an allogeneic therapy is its potential to induce graft-versus-host disease in the recipient, a potentially life-threatening side effect in which the donor’s immune system sees the patient’s cells and organs as threats, and launches damaging attacks against them.
To avoid this reaction, Precision uses a single-step genetic engineering technique, using its proprietary ARCUS system, in which the CAR gene specifically replaces a pre-existing gene for a protein called T-cell receptor (TCR), which is involved in T-cell recognition. Removing TCR has been shown in early lab and animal tests to eliminate the graft-versus-host disease response.
“In preclinical disease models, PBCAR269A has demonstrated no evidence of graft-versus-host disease at doses that resulted in potent anti-tumor activity,” said Chris Heery, chief medical officer of Precision. “There remains significant unmet need in the treatment of relapsed/refractory multiple myeloma, and we are excited to begin clinical trials with an off-the-shelf CAR T therapy candidate in this setting.”
The open-label Phase 1/2a clinical trial will enroll up to 48 patients with relapsed or refractory myeloma who failed to respond to two prior myeloma therapies, including an immunomodulatory agent like Revlimid (lenalidomide) and a protease inhibitor such as Velcade (bortezomib).
Trial locations have not yet been announced by Precision; general contact information is available here.
Before initiating treatment with the CAR T-cells, all enrolled will be give a chemotherapy regimen — consisting of fludarabine and cyclophosphamide — to prepare the body for the engineered cells. The chemotherapy not only eliminates cancer cells, but also creates room for the CAR T-cells to expand.
The clinical trial will follow the standard “3+3 model” to determine the maximum dose tolerated by patients. In this model, patients are placed in groups of three, and each subsequent group is given a slightly higher dose of PBCAR29A. Clinicians will monitor patients for any adverse reactions.
After an optimal dose has been established in Phase 1, researchers will enroll additional patients to continue studying that dose’s safety and evidence of efficacy. The effectiveness of PBCAR29A will be assessed by examining the proportion of patients who experience tumor reduction — a measure called objective response rate — and duration of response.
Exploratory efficacy measures include changes in circulating tumors cells, the amount of CAR T-cells in circulation at given time points, and measures of immune system activation.
Participants will be followed for up to 15 years in a separate, long-term study after completing this trial.
“We have now moved three CAR T programs from preclinical to clinical stage development since April 2019, and we look forward to continuing to advance our allogeneic CAR T portfolio to bring these novel therapeutic candidates to patients,” Kane said.
In addition to PBCAR269A, Precision has to other CAR T-cell products in Phase 1/2a clinical testing: PBCAR0191 is being tested (NCT03666000) in patients with B-cell acute lymphoblastic leukemia and non-Hodgkin’s lymphoma; and PBCAR20A will soon begin testing (NCT04030195) in people with non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma.