An early study adding palbociclib to ibrutinib in previously treated patients with mantle cell lymphoma (MCL) showed a higher complete response rate than what has previously been reported for single-agent ibrutinib, according to investigators.
Results from the phase 1 trial (NCT02159755) support preclinical models, suggesting that the CDK4/6 inhibitor palbociclib may be able to help overcome resistance to ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK).
These findings set the stage for an ongoing phase 2 multicenter study, reported lead author Peter Martin, MD, of Weill Cornell Medicine in New York and his colleagues.
The present study involved 27 patients with previously treated MCL, the investigators wrote in Blood. Of these, 21 were men and 6 were women, all of whom had adequate organ and bone marrow function, good performance status, and no previous treatment with CDK4/6 or BTK inhibitors.
Patients were randomly grouped into five dose levels of each drug: Ibrutinib doses ranged from 280-560 mg, and palbociclib from 75-125 mg. Ibrutinib was given daily and palbociclib was administered for 21 out of 28 days per cycle. Therapy continued until withdrawal, unacceptable toxicity, or disease progression.
The primary objective was to determine phase 2 dose. Secondarily, the investigators sought to determine activity and toxicity profiles. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1-21 of each 28-day cycle.
Across all patients, the complete response rate was 37%, compared with 21% for ibrutinib monotherapy in a previous trial. About two-thirds of patients had a response of any kind, which aligns closely with the overall response rate previously reported for ibrutinib alone (67% vs. 68%). After a median follow-up of 25.6 months in survivors, the 2-year progression free survival was 59.4%. The two-year overall survival rate was 60.6%.
The dose-limiting toxicity was grade 3 rash, which occurred in two out of five patients treated at the highest doses. The most common grade 3 or higher toxicities were neutropenia (41%) and thrombocytopenia (30%), followed by hypertension (15%), febrile neutropenia (15%), lung infection (11%), fatigue (7%), upper respiratory tract infection (7%), hyperglycemia (7%), rash (7%), myalgia (7%), and increased alanine transaminase/aspartate aminotransferase (7%).
“Although BTK-inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear,” the investigators wrote, noting that a phase 2 trial (NCT03478514) is currently underway and uses the maximum tolerated doses.
The phase 1 trial was sponsored by the National Cancer Institute. Study funding was provided by the Sarah Cannon Fund at the HCA Foundation. The investigators reported financial relationships with Janssen, Gilead, AstraZeneca, Celgene, Karyopharm, and others.
SOURCE: Martin P et al. Blood. 2019 Jan 28. doi: 10.1182/blood-2018-11-886457.