Phase II Study of Brentuximab Vedotin Plus Ibrutinib for Patients with Relapsed/Refractory Hodgkin Lymphoma

Background:

Brentuximab vedotin (BV), an antibody drug conjugate (ADC), selectively delivers anti-tubulin agent monomethyl auristatin E (MMAE) to CD 30+ cells. In a a multi-center phase II trial in patients with relapsed/refractory Hodgkin lymphoma (HL), BV showed an overall response rate (ORR) of 75%, a complete response (CR) rate of 34%, and a median duration of response (DOR) of 6.7 months (Younes A et al, JCO 2012). Although this drug has high ORR in HL, the CR rate and the DOR can be improved.

Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has demonstrated antitumor activity in B-cell lymphomas. Ibrutinib is also an irreversible inhibitor of interleukin-2-inducible kinase (ITK), which has a critical role in T cell signaling. Inhibition of ITK leads to increased Th1 based immune response (Dubovsky JA, Blood 2013). As a single agent at standard dose, ibrutinib does not have antitumor activity in HL cell line (Figure 1). However, we have shown that standard dose ibrutinib is synergistic with BV in L428, a HL cell line (Figure 1). Based on our preclinical model, we hypothesize that ibrutinib may enhance the antitumor activity of BV in HL patients. It is also possible Ibrutinib may enchance the activity of BV through ITK inhibition of T cells in the HL microenvironment. Thus we designed and conducted a phase II trial using the combination of ibrutinib plus BV in patients with R/R HL. We report the planned interim analysis of efficacy and safety.

Patients and Methods:

This is a prospective, multicenter phase II trial with a 3-patient lead-in cohort in patients with relapsed/refractory HL. All patients must be > 15 years old and have biopsy proven relapsed/refractory HL. Patients are treated with 1.8 mg/kg of BV intravenously every 3 weeks and ibrutinib 560 mg PO daily (420 mg PO daily in the lead-in cohort). Patients could have received prior BV. The primary endpoint was the CR rate according to Lugano 2014. Secondary endpoints were toxicities, ORR, duration of response, and, BTK/ITK receptor occupancy, and changes in T/B/NK cell subsets in peripheral blood.

Results:

Sixteen out of 39 patients were accrued thus far, all 16 pts were evaluable for toxicity, and 13 patients were evaluable for efficacy (3 lead-in pts excluded). The baseline characteristics (Figure 1) are: male (56%), Caucasian (75%), median age of 33 (17-69), stage III/IV at diagnosis (50%), primary refractory to induction (50%), refractory to last therapy (37%), and 4 patients had prior BV (25%). The overall best response (CR+PR) rate was 69%, CR rate was 46%, stable disease rate was 31%, and no progressive disease (PD) was seen. The disease control rate (CR+PR+SD) was 100%. One patient who was refractory to prior BV achieved a PR, and an additional patient who had a previous best response of PR to BV now achieved a CR.

Treatment was well tolerated. There were no Grade 4 events. Grade 3 possibly-related toxicities included neutropenia (n=2) and hypokalemia (n=1). Grade I/II possibly related toxicities >20% included diarrhea (n=8, 7 grade 1), nausea (n=6, all grade 1), fatigue (n=5, all grade 1), rash (n=5, 4 grade 1), and thrombocytopenia (n=4, all grade 1).

Conclusion:

The combination of BV + ibrutinib is well tolerated. Although the ORR of 69% maybe similar to BV alone, the CR of 46% and disease control rate of 100% appears promising. Especially encouraging is the 1 PR and 1 CR seen in patients previously exposed to BV. The study has met the interim analysis endpoint and warrants further accrual to investigate the final CR rate.

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