A multiple myeloma (MM) drug candidate with a new mode of action from Imperial College London is now in Phase II patient trials following positive Phase I results. 

The first-in-class investigational drug DTP3 is designed to treat MM and other cancers, including diffuse large B-cell lymphoma (DLBCL), by inhibiting the GADD45β/MKK7 signalling complex, a mechanism that most myelomas require for their survival. 

In addition to treating refractory MM, DTP3 is intended to form part of a frontline polytherapy with other drugs aiming to curb treatment-induced drug resistance. 

The new drug builds on research into the NF-κB pathway, which is used to mount an immune response to injury and infection but is often hijacked by cancers for their own survival. 

While NF-κB has attracted major interest as a potential target for cancer drugs since the 1990s, candidates designed to inhibit it have failed due to serious on-target side effects. 

Research by Professor Franzoso and colleagues at Imperial College London has raised hope that some cancers could instead be treated by targeting a mechanism located downstream of NF-κB. 

Phase I trial showed early evidence of efficacy 

The team found that most myelomas use NF-κB to upregulate the protein GADD45β, which binds to protein kinase MKK7 to prevent apoptosis, a process that causes cancer cells to self-destruct. The research found that the GADD45β/MKK7 complex is critical to the survival of these cancer cells, but importantly not to healthy cells. 

These insights led to the development of DTP3, which proved highly effective in pre-clinical tests at selectively killing cancer cells in animal models and myeloma cells from patients, while leaving healthy cells unharmed. 

The Phase I dose escalation trial tested the tolerability of DTP3 in 15 patients, 14 with refractory MM and one with DLBCL, at doses ranging from 2mg/kg to 67mg/kg. It found that the drug was well tolerated at doses of up to 45mg/kg. 

The trial also yielded preliminary evidence of efficacy. It showed the drug activated apoptosis selectively in the cancer cells in around 50% of patients. One of two patients with MM who were given DTP3 at the dose of 30mg/kg demonstrated a Very Good Partial Response with no signs of toxicity, and cancers remained stable in five of the eight patients treated at lower doses ranging from 6 to 20mg/kg. 

Dr Aristeidis Chaidos, Consultant Haematologist at Hammersmith Hospital and Honorary Clinical Senior Lecturer at Imperial College London, the trial’s chief investigator, said: “The Phase I data shows that DTP3 is very well tolerated in patients. It is also highly encouraging to see that among this cohort of patients with heavily refractory cancers – who had received multiple previous lines of treatment and stopped responding – the cancer was strongly reduced in one of two cases treated at 30mg/kg. We are hopeful of finding strong evidence of reduction in cancer burden in Phase II now that we have identified a clinically effective dose.”