Allogene, SpringWorks Collaborate to Test ALLO-715, Nirogacestat Combo for RRMM

Allogene Therapeutics and SpringWorks Therapeutics have launched a clinical trial collaboration to conduct a Phase 1 study assessing an ALLO-715 combination therapy in people with relapsed or refractory multiple myeloma.  

The trial will test ALLO-715, Allogene’s CAR T-cell therapy, plus SpringWorks’ experimental gamma secretase inhibitor, nirogacestat. It is expected to begin in the second half of 2020, pending discussions with regulatory authorities, Allogene said in a press release.

Chimeric antigen receptor T-cell therapy, commonly known as CAR T-cell therapy, is a type of treatment that normally involves collecting a patient’s immune T-cells and modifying them in the lab. The cells are treated so that they start producing a chimeric antigen receptor (CAR), a protein construct that helps these cells recognize and target specific cancer proteins. The modified cells are then given back to the patient by infusion.

ALLO-715 is a CAR T-cell therapy designed to target the B-cell maturation antigen (BCMA) molecule, found at high levels in multiple myeloma cells. Unlike more common versions of CAR T-cells, ALLO-715 uses immune T-cells harvested from unrelated donors (allogeneic), allowing the therapy to be offered off-the-shelf, or not specially made.

While this allows patients to receive the treatment much faster, a donor-derived product raises the potential problem of graft-versus-host disease (GvHD). This is a serious complication in which the transplanted T-cells from the healthy donors start attacking the host’s body.

Thus, Allogene’s researchers engineered ALLO-715’s cells to attack only BCMA-positive cells. They also included a “safety switch,” which allows them to destroy the engineered cells in the presence of rituximab, if needed.

“Autologous CAR T therapy has shown the potential for engineered cell therapy to treat multiple myeloma and provide significant benefits to patients,” said David Chang, MD, PhD, president, CEO, and co-founder of Allogene Therapeutics.

“We believe allogeneic CAR T therapy is the next frontier in genetically engineered cell therapy for the treatment of cancer,” Chang said.

ALLO-715 is currently being evaluated in the UNIVERSAL Phase 1 clinical trial (NCT04093596) in people with multiple myeloma who failed to respond to treatment (refractory), or whose cancer progressed after first responding to prior therapy (relapsed).

Under the collaboration, the researchers will advance a second Phase 1 trial in a similar population of multiple myeloma patients. This trial will test the CAR T-cell therapy in combination with the oral gamma secretase inhibitor nirogacestat.

Gamma secretase is an enzyme that cleaves and detaches BCMA from the surface of myeloma cells. By inhibiting gamma secretase, nirogacestat is expected to increase the amount of BCMA on the surface of cancer cells and improve the efficacy of BCMA-targeted therapies like ALLO-715.

A combination of similar therapies — Juno‘s BCMA CAR T-cell therapy and another investigational gamma secretase inhibitor, JSMD194 — led to responses in 100% of relapsed or refractory multiple myeloma patients in a Phase 1 trial (NCT03502577). Five of the six patients in the trial also were negative for minimal residual disease — the small number of cancer cells that remain after treatment, and could cause relapse in the future.

“Gamma secretase inhibition has emerged as a clinically validated mechanism to potentiate BCMA therapies and we believe that nirogacestat has the potential to become a cornerstone of BCMA combination therapy for patients with multiple myeloma,” said Saqib Islam, CEO of SpringWorks.

“The search to find long-lasting and potentially curative therapies for patients with multiple myeloma continues to evolve,” Chang said.

“We are pleased with the progress of our ALLO-715 Phase 1 UNIVERSAL trial and are excited to explore the combination of ALLO-715 with nirogacestat as a means to further unlock the potential of allogeneic CAR T therapy in this disease,” he said.

As per the agreement, Allogene will sponsor and conduct the Phase 1 trial to determine the safety, tolerability, and efficacy of the combination therapy, and will be responsible for the costs associated with the study. Allogene and SpringWorks will form a combined development team that will supervise the clinical study.

“We are delighted to partner with Allogene, a pioneer in the allogenic cell therapy field, to further explore nirogacestat in combination with an ‘off-the-shelf’ CAR T therapy for these patients where the need for treatment options remains great,” Islam said.

SpringWorks is currently recruiting patients for a global Phase 3 clinical trial (NCT03785964) that will evaluate nirogacestat in adults with progressing desmoid tumors — abnormal growth that arises from connective tissue. In this trial, nirogacestat is being assessed for its ability to block the activation of the Notch signaling pathway, known to play a key role in cancer.