US-based Celldex Therapeutics has started a Phase I/II safety pilot and expansion trial evaluating the investigational combination of its fully human monoclonal antibody, varlilumab and ipilimumab in patients with Stage III or IV metastatic melanoma.

Varlilumab targets CD27, a critical co-stimulatory molecule in the immune activation cascade, while Ipilimumab is a recombinant, human monoclonal antibody that blocks CTLA-4.

Marketed as Yervoy by Bristol-Myers Squibb (BMS), Ipilimumab is approved by the US Food and Drug Administration (FDA) to treat unresectable or metastatic melanoma.

In the Phase II portion of the trial, patients with tumours that express NY-ESO-1 will also receive CDX-1401, Celldex’s off-the-shelf antibody-based dendritic cell vaccine that targets tumours expressing the NY-ESO-1 oncoprotein.

"We believe sophisticated combination approaches centred on immunotherapy hold significant promise for the treatment of cancer."

In Phase I/II, the three agents were specifically selected as they intervene at key points of immune regulation and because the company has observed improved activity in preclinical trials when varlilumab is combined with either checkpoint inhibitors or with vaccines.

In addition, the trial will also build on previous clinical data which suggests that CDX-1401 may predispose patients to better outcome on checkpoint inhibitors, including ipilimumab.

The trial’s Phase I portion is designed to evaluate the safety and tolerability of varlilumab at 0.3 and 3.0mg/kg in combination with ipilimumab at 3mg/kg administered every three weeks to identify a recommended dose for the Phase II portion of the trial.

The Phase II portion will include two groups, one comprised of patients who are NY-ESO-1 positive and the other comprised of patients who are NY-ESO-1 negative.

In this portion, patients who are NY-ESO-1 positive will also receive CDX-1401 dosed at 1mg every three weeks in addition to varlilumab and ipilimumab.

Celldex Therapeutics executive vice-president and chief medical officer Thomas Davis said: "We believe sophisticated combination approaches centred on immunotherapy hold significant promise for the treatment of cancer and, to this end, are committed to exploring novel combinations across a broad array of mechanisms and indications.

"This latest trial marks the third Phase I/II combination study that varlilumab has entered and the first three-drug combination study."

The primary objective for both groups is objective response rate up to 24 weeks (ORR6) using standard, modified World Health Organization (WHO) response criteria.

The Phase II trials’ secondary objectives include safety and tolerability, immunogenicity, pharmacokinetics and further evaluation of anti-tumour activity across a broad range of endpoints.

Varlilumab is currently being evaluated in three Phase I/II combination trials and several additional combination trials will be started in 2015.