A Phase 1 trial testing the combination of ADCT-402 (loncastuximab tesirine) with Imbruvica (ibrutinib) for advanced diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL) has dosed the first patient.
Patient enrollment, for a planned total of 60 participants, is ongoing in the U.S. and Belgium. More information on contacts and locations can be found here.
“Unfortunately, a significant number of patients with B-cell malignancies will relapse after initial treatment. As the prognosis for these patients is poor, it is important to evaluate potential viable new treatments for relapsed or refractory diffuse large B-cell lymphoma and mantle cell lymphoma, such as the combination of ADCT-402 and ibrutinib we are studying in this Phase I trial,” Julien Depaus, MD, a trial investigator, said in a press release.
The open-label trial (NCT03684694) includes a dose escalation phase, followed by a dose expansion stage. In the first part, patients will receive two cycles of ADCT-402 — given in ascending doses — together with Imbruvica, and may continue receiving Imbruvica for up to one year.
After assessing the combo’s safety and tolerability, patients in the second part may receive either the combo therapy or a sequential regimen, where ADCT-402 is administered first followed by Imbruvica.
This second part will include two cohorts, one for DLBCL and one for MCL, each composed of 20 patients. It is expected to collect additional safety and early anti-tumor activity data at the maximum tolerated dose.
Imbruvica (ibrutinib), jointly developed and commercialized by Janssen and Pharmacyclics, is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor. BTK helps B cells stay alive and divide, but Imbruvica blocks these signals in malignant B cells, thereby stopping or slowing the progression of cancer.
ADCT-402, developed by ADC Therapeutics, belongs to a class of compounds known as antibody-drug conjugates, consisting of a cancer-targeting antibody bound to a toxic molecule. The investigational therapy binds to CD19, a protein found on the surface of many types of blood cancer cells, and carries a toxin called pyrrolobenzodiazepine, which is able to kill cancer cells.
ADCT-402 is being tested in an ongoing Phase 1 trial (NCT02669017) in 183 B-cell non-Hodgkin’s lymphoma patients who failed prior therapies. Results to date have shown that 60.3% of patients receiving a dose of 120 µg/kg or higher responded to treatment — including 35.3% complete responses.
In the subset of 49 patients with DLBCL treated with 120 µg/kg or higher doses, 55.1% of patients responded to the treatment, including 36.7% complete responses. For those with follicular lymphoma and MCL, responses were seen in 78.6% and 46.7% of patients, respectively. After a median of 8.7 months, more than half the patients in both groups were still responding to the treatment.
“The data we presented from our 183-patient first-in-human clinical trial of ADCT-402 demonstrated its encouraging safety profile and anti-tumor activity as a single agent against relapsed or refractory diffuse large B-cell lymphoma and mantle cell lymphoma,” said Jay Feingold, MD, PhD, chief medical officer and senior vice president of clinical development at ADC Therapeutics.
“Now, in our second combination trial of ADCT-402, we look forward to exploring whether ADCT-402 and ibrutinib, both of which target B-cell cancers with different mechanisms of action, may increase the response rate and durability of response compared to the effects of these compounds as single agents,” he said.
ADCT-402 is also being tested in a pivotal Phase 2 trial (NCT03589469) in patients with relapsed or refractory DLBCL. This study — still recruiting participants — is expected to support the submission of a biologics license application (BLA) to the U.S. Food and Drug Administration for this indication.
Also, an ongoing Phase 1 trial (NCT03685344) is testing a combination of ADCT-402 and AstraZeneca’s Imfinzi (durvalumab) in DLBCL, MCL, and follicular lymphoma patients who have relapsed or refractory disease and have failed or been intolerant to standard treatment.