First Patient Dosed in Trial Testing Belantamab Mafodotin, Nirogacestat Combo in RRMM Patients

A Phase 1b clinical trial evaluating GlaxoSmithKline (GSK)’s belantamab mafodotin, in combination with SpringWorks Therapeutics’ nirogacestat, in people with relapsed or refractory multiple myeloma, has dosed its first patient, SpringWorks announced.

The safety and preliminary effectiveness of this combination are being assessed as a sub-study in GSK’s ongoing DREAMM-5 platform trial (NCT04126200).

“We are delighted to have reached this important milestone of dosing the first patient in this collaborative trial with GSK,” Saqib Islam, SpringWorks’ CEO, said in a press release.

“We look forward to generating clinical data to test the hypothesis that adding nirogacestat to belantamab mafodotin could lead to better clinical outcomes for patients,” Islam said.

An antibody-drug conjugate, belantamab mafodotin comprises an antibody targeting the B-cell maturation antigen (BCMA) — a protein found at high levels on the surface of myeloma cells — bound to a cancer-killing agent called auristatin F. Once the antibody binds to BCMA on the surface of cancer cells, auristatin F is released into the cells, promoting their death.

Its therapeutic effects currently are being investigated in heavily treated patients with multiple myeloma that has relapsed or failed to respond to treatment (refractory).

Nirogacestat is an oral, small molecule that works by blocking gamma secretase, an enzyme that cleaves and detaches BCMA from the surface of myeloma cells. By inhibiting the enzyme’s activity, nirogacestat is expected to increase the amount of BCMA on the surface of cancer cells and boost the effectiveness of BCMA-targeted therapies, such as belantamab mafodotin.

In agreement, preclinical data showed that adding nirogacestat to belantamab mafodotin resulted in up to about 3,000 times greater cell death in human multiple myeloma cells, compared with belantamab mafodotin alone.

The open-label, international DREAMM-5 platform study is assessing the effects of belantamab mafodotin, in combination with other anti-cancer therapies (each combination as a sub-study), in adults with relapsed or refractory myeloma.

The trial is still recruiting about 460 participants at sites in the U.S., Australia, Canada, and Europe. More information on contacts and locations is available here.

The Phase 1b trial, one of its sub-studies, is evaluating the safety, tolerability, and preliminary effectiveness of belantamab mafodotin, in combination with nirogacestat.

In the trial’s dose-exploration phase, an optimal dose of each therapy in combination will be determined to move to its expansion phase, which will compare the clinical effects of the combination therapy with those of belantamab mafodotin alone in additional myeloma patients.

The trial is the result of a global clinical trial collaboration agreement between SpringWorks and GSK, settled last year. As per the agreement, GSK is sponsoring and conducting the trial, being responsible for all its costs, except expenses related to nirogacestat’s manufacturing and intellectual property rights. The companies have formed a joint development committee to help manage and oversee the trial.

“SpringWorks is focused on advancing a comprehensive strategy to evaluate the ability of nirogacestat to potentiate BCMA-directed therapies across modalities with the goal of making nirogacestat a cornerstone of BCMA combination therapy for patients with multiple myeloma,” Islam said.

Nirogacestat also is being evaluated as a potential treatment for people with desmoid tumors, which are abnormal growths that arise from connective tissue and for which there are no approved therapies. Its potential therapeutic benefits in this context are thought to be related to its ability to block the Notch signaling pathway, known to play a key role in cancer.

SpringWorks is currently recruiting patients for a global Phase 3 clinical trial (NCT03785964) testing nirogacestat in adults with progressing desmoid tumors.